The BAF complex inhibitor pyrimethamine reverses HIV-1 latency in people with HIV-1 on antiretroviral therapy.

Reactivation of the latent HIV-1 reservoir is a first step toward triggering reservoir decay. Here, we investigated the impact of the BAF complex inhibitor pyrimethamine on the reservoir of people living with HIV-1 (PLWH). Twenty-eight PLWH on suppressive antiretroviral therapy were randomized (1:1:1:1 ratio) to receive pyrimethamine, valproic acid, both, or no intervention for 14 days. The primary end point was change in cell-associated unspliced (CA US) HIV-1 RNA at days 0 and 14. We observed a rapid, modest, and significant increase in (CA US) HIV-1 RNA in response to pyrimethamine exposure, which persisted throughout treatment and follow-up. Valproic acid treatment alone did not increase (CA US) HIV-1 RNA or augment the effect of pyrimethamine. Pyrimethamine treatment did not result in a reduction in the size of the inducible reservoir. These data demonstrate that the licensed drug pyrimethamine can be repurposed as a BAF complex inhibitor to reverse HIV-1 latency in vivo in PLWH, substantiating its potential advancement in clinical studies.

Characteristics and short- and long-term direct medical costs among adults with timely and delayed presentation for HIV care in the Netherlands.

INTRODUCTION: In Europe, half of people living with HIV (PLWH) present late to care, with associated higher morbidity and mortality. This study aims to assess short- and long-term costs of HIV-care based on time of presentation and identify other factors contributing to higher costs in the first and fifth year after antiretroviral therapy (ART) initiation. MATERIAL AND METHODS: We included ATHENA cohort data which prospectively includes 98% of PLWH in the Netherlands. PLWH who initiated ART in 2013 were included and followed over five years. PLWH were divided in three categories based on CD4 cell-count at time of ART initiation: timely presentation (CD4>350cells/µL), late presentation (CD4 200-350cells/µL or >350cells/µL with AIDS-defining illness) and very late presentation (CD4<200cells/µL). The total HIV-care cost was calculated distinguishing ART medication and non-ART medication costs (hospitalization, outpatient clinic visits, co-medications, and HIV-laboratory tests). RESULTS: From 1,296 PLWH, 273 (21%) presented late and 179 (14%) very late. Nearly half of those who entered HIV-care in a very late stage were of non-Dutch origin, with 21% originating from sub-Saharan Africa. The mean cost per patient in the first year was €12,902 (SD€11,098), of which about two-thirds due to ART (€8,250 (SD€3,142)). ART costs in the first and fifth year were comparable regardless of time of presentation. During the first year on treatment, non-ART medication costs were substantially higher among those with late presentation (€4,749 (SD€8,009)) and very late presentation (€15,886 (SD€ 21,834)), compared with timely presentation (€2,407(SD€4,511)). Higher non-ART costs were attributable to hospitalization and co-medication. The total non-ART costs incurred across five years on treatment were 56% and 246% higher for late and very late presentation respectively as compared to timely presentation. CONCLUSION: Very late presentation is associated with substantial costs, with non-ART costs nearly seven times higher than for those presenting timely. Hospitalization and co-medication costs are likely to continue to drive higher costs for individuals with late presentation into the future. Programs that identify individuals earlier will therefore likely provide significant short- and long-term health cost savings.

HIV transmission among acutely infected participants of a Dutch cohort study 2015-2021 is not associated with large, clustered outbreaks.

OBJECTIVE: Timely identification of acute or early HIV infection (AEHI) is important to help prevent onward transmission, and understanding the number of secondary infections resulting from individuals with AEHI is key to planning HIV prevention services and case finding. DESIGN: We performed a phylogenetic investigation of a dense sample of individuals with AEHI who took part in the Netherlands Cohort Study on Acute HIV infection (NOVA) in the Netherlands during 2015-2021. METHODS: Transmission clusters were identified using phylogenetic analyses based on HIV pol sequences. The Tamura-Nei model was used to estimate genetic distance. A number of 1000 bootstraps was used to check the reliability of clustering using maximum likelihood. A cluster was defined as having a bootstrap value of at least 95% and a genetic distance of at most 1.5%. Sensitivity analyses using different values for the bootstrap and genetic distance were performed to study the reproducibility of the clustering. RESULTS: Of the 156 participants included in NOVA between July 2015 and April 2021, 134 individuals for whom baseline characteristics and genotypic resistance data at baseline were available could be included. We identified 10 clusters, but the majority of persons (111/134) were not part of a cluster, suggesting mainly independent transmission events. CONCLUSION: Mainly independent transmission events among a study population consisting predominantly of MSM in a low-incidence high-resource setting is likely the result of active AEHI case finding and direct start of treatment, and the roll-out over recent years of preventive measures such as preexposure prophylaxis.

HIV-1 resistance against dolutegravir fluctuates rapidly alongside erratic treatment adherence: a case report.

OBJECTIVES: We report a case of incomplete HIV-1 suppression on a dolutegravir, lamivudine, and abacavir single-tablet regimen with the emergence of the H51Y and G118R integrase resistance mutations. METHODS: Integrase sequencing was performed retrospectively by Sanger and next-generation sequencing. Rates of emergence and decline of resistance mutations were calculated using next-generation sequencing data. Dolutegravir plasma concentrations were measured by ultra-performance liquid chromatography-tandem mass spectrometry. The effects of H51Y and G118R on infectivity, fitness, and susceptibility to dolutegravir were quantified using cell-based assays. RESULTS: During periods of non-adherence to treatment, mutations were retrospectively documented only by next-generation sequencing. Misdiagnosis by Sanger sequencing was caused by the rapid decline of mutant strains within the retroviral population. This observation was also true for a M184V lamivudine-resistant reverse transcriptase mutation found in association with integrase mutations on single HIV genomes. Resistance rebound upon treatment re-initiation was swift (>8000 copies per day). Next-generation sequencing indicated cumulative adherence to treatment. Compared to WT HIV-1, relative infectivity was 73%, 38%, and 43%; relative fitness was 100%, 35%, and 10% for H51Y, G118R, and H51Y+G118R viruses, respectively. H51Y did not change the susceptibility to dolutegravir, but G188R and H51Y+G118R conferred 7- and 28-fold resistance, respectively. CONCLUSION: This case illustrates how poorly-fit drug-resistant viruses wax and wane alongside erratic treatment adherence and are easily misdiagnosed by Sanger sequencing. We recommend next-generation sequencing to improve the clinical management of incomplete virological suppression with dolutegravir.

Persistent Transmission of HCV among Men Who Have Sex with Men despite Widespread Screening and Treatment with Direct-Acting Antivirals.

BACKGROUND: In the Netherlands, unrestricted access to direct-acting antivirals (DAAs) halved the incidence of acute hepatitis C virus (HCV) infections among HIV-infected men who have sex with men (MSM). To develop strategies that can further reduce the spread of HCV, it is important to understand the transmission dynamics of HCV. We used phylogenetic analysis of a dense sample of MSM to provide insight into the impact of unrestricted access to DAAs on HCV transmission in the Netherlands and in Belgium. METHODS: We included 89 MSM that were recently infected with HCV genotype 1a in ten Dutch and one Belgian HIV treatment centers. Sequences were generated using next gene sequencing and Sanger sequencing. Maximum likelihood phylogenetic analysis (general time reversible model) was performed on concatenated NS5A and NS5B sequences and a reference set of 389 highly similar control sequences selected from GenBank. A cluster was based on a minimum bootstrap support of 90% and a 3% genetic distance threshold. RESULTS: We found that 78 (88%) of individuals were part of seven major clusters. All clusters included individuals from across the study region, however, different cities were part of different clusters. In three clusters, HIV-negative MSM clustered with sequences from HIV-positive MSM. All clusters that were observed before the introduction of DAAs persisted after unrestricted access to DAAs became available. CONCLUSION: Recently acquired HCV infections among MSM in the Netherlands and Belgium are strongly clustered and therefore highly suitable for targeted prevention strategies, such as contact tracing and partner notification. Importantly, despite an HCV incidence reduction after high DAA uptake and continuously monitoring, HCV transmission persisted in the same clusters.

Significant Impact of Coronavirus Disease 2019 (COVID-19) on Human Immunodeficiency Virus (HIV) Care in Hospitals Affecting the First Pillar of the HIV Care Continuum.

During COVID-19 lockdown, the in-hospital number of HIV indicator conditions decreased disproportionally compared with other non-COVID-19 diseases, which was accompanied by reduced HIV testing rates, number and proportion of positive HIV tests, and new HIV referrals, with more late presentation after lockdown cessation, indicating a significantly impacted HIV care continuum.

Quality of life among people living with HIV in England and the Netherlands: a population-based study.

BACKGROUND: HIV is now considered a chronic condition, and people living with HIV, when treated, have a similar life expectancy as compared to the general population. Consequently, improving and ensuring a good health-related quality of life (HrQoL) among people living with HIV (people living with HIV) is increasingly important and has risen on the global agenda in recent years. A 'fourth 90' as 90% of people with viral load suppression have a good HrQoL should therefore be adopted alongside the other 90-90-90 targets. This study aims to report the progress on HrQoL as the 'fourth 90' and compare against the general population in the Netherlands and England. METHODS: In the Netherlands, individuals attending the HIV outpatient clinic of a tertiary hospital were asked to complete the EQ-5D-5L from June 2016 until December 2018. In England, individuals attending one of 73 HIV outpatient clinics were randomly sampled to complete the Positive Voices survey, which included the EQ-5D-5L, from January to September 2017. HrQoL scores were combined with demographic data and compared to general population data. FINDINGS: The EQ-5D-5L was filled-out by 895 people living with HIV in the NL and 4,137 in England. HrQoLutility was 0·85 among Dutch and 0·83 among English people living with HIV. This equated to 98% and 94% of the general population HrQoLutility in the Netherlands and England, respectively. Of the EQ-5D domains, anxiety/depression was mostly affected, with one-third in Dutch (35%) and almost half (47%) of English people living with HIV reporting symptoms. This was higher compared to their respective general populations (21% NL and 31% England). INTERPRETATION: Overall, HrQoLutility for people living with HIV was high in both countries and highly comparable to the general populations Nevertheless, there should be an increased focus on anxiety and depression in the people living with HIV population The EQ-5D-5L proved an easy HrQoL measurement tool and identified areas for improvement by social and behavioural interventions. FUNDING: The study received funding (unrestricted grants) from: Gilead sciences, ViiV Healthcare, MSD, and Jansen pharmaceuticals.

Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease-2019 (COVID-19).

Key questions in COVID-19 are the duration and determinants of infectious virus shedding. Here, we report that infectious virus shedding is detected by virus cultures in 23 of the 129 patients (17.8%) hospitalized with COVID-19. The median duration of shedding infectious virus is 8 days post onset of symptoms (IQR 5-11) and drops below 5% after 15.2 days post onset of symptoms (95% confidence interval (CI) 13.4-17.2). Multivariate analyses identify viral loads above 7 log10 RNA copies/mL (odds ratio [OR] of 14.7 (CI 3.57-58.1; p < 0.001) as independently associated with isolation of infectious SARS-CoV-2 from the respiratory tract. A serum neutralizing antibody titre of at least 1:20 (OR of 0.01 (CI 0.003-0.08; p < 0.001) is independently associated with non-infectious SARS-CoV-2. We conclude that quantitative viral RNA load assays and serological assays could be used in test-based strategies to discontinue or de-escalate infection prevention and control precautions.

The European Prevalence of Resistance Associated Substitutions among Direct Acting Antiviral Failures.

Background: Approximately 71 million people are still in need of direct-acting antiviral agents (DAAs). To achieve the World Health Organization Hepatitis C elimination goals, insight into the prevalence and influence of resistance associated substitutions (RAS) is of importance. Collaboration is key since DAA failure is rare and real-life data are scattered. We have established a European collaboration, HepCare, to perform in-depth analysis regarding RAS prevalence, patterns, and multiclass occurrence. Methods: Data were extracted from the HepCare cohort of patients who previously failed DAA therapy. Geno-and subtypes were provided by submitters and mostly based on in-house assays. They were reassessed using the Comet HCV subtyping tool. We considered RAS to be relevant if they were associated with DAA failure in vivo previously reported in literature. Results: We analyzed 938 patients who failed DAA therapy from ten different European countries. There were 239 genotypes (GT) 1a, 380 GT1b, 19 GT2c, 205 GT3a, 14 GT4a, and 68 GT4d infections. Several unusual subtypes (n = 15) (GT1b/g/l, GT3b, GT4k/n/r/t) were present. RAS appeared in over 80% of failures and over a quarter had three or more RAS. Multiclass RAS varied over target region and genotype between 0-48%. RAS patterns such as the Q30R + L31M and Q30R + Y93H in GT1a, the L31V + Y93H and L31V + Y93H for GT1b, and A30K + L31M and A30K/V + Y93H for GT3a all occurred with a prevalence below 5%. Conclusion: RAS occur frequently after DAA failures and follow a specific genotype and drug related pattern. Interpretation of the influence of RAS on retreatment is challenging due to various patterns, patients' characteristics, and previous treatment history. Moving towards HCV elimination, an ongoing resistance surveillance is essential to track the presence of RAS, RAS patterns and gather data for a re-treatment algorithm.

Feasibility of Four Interventions to Improve Treatment Adherence in Migrants Living with HIV in The Netherlands.

We evaluated the feasibility and efficacy of four existing interventions to improve adherence to them in migrants living with HIV (MLWH): directly administered antiretroviral therapy (DAART), group medical appointments (GMA), early detection and treatment of psychological distress, and peer support by trained MLWH. At baseline and after the interventions, socio-demographic characteristics, psychosocial variables, and data on HIV treatment adherence were collected. The two questionnaires were completed by 234/301 (78%) MLWH included at baseline. Detectable HIV RNA decreased (from 10.3 to 6.8%) as did internalized HIV-related stigma (from 15 to 14 points), and self-reported adherence increased (between 5.5 and 8.3%). DAART and GMA were not feasible interventions. Screening of psychological distress was feasible; however, follow-up diagnostic screening and linkage to psychiatric services were not. Peer support for and by MLWH was feasible. Within this small intervention group, results on HIV RNA < 400 copies/mL (decrease of 23.6%) and outpatient clinic attendance (up to 20.4% kept more appointments) were promising.

Dried blood spot cards: A reliable sampling method to detect human antibodies against rabies virus.

BACKGROUND: Although preventable by vaccination for more than a century, rabies virus still causes numerous fatalities every year. To determine antibody levels in humans, blood collected with a finger prick and applied on dried blood spot (DBS) cards is an alternative for venipuncture. The use of DBS is specifically valuable in remote areas, as it is easy to perform, store and transport. Therefore, the technique is frequently used for epidemiological studies of tropical diseases. Up to present, determination of rabies virus antibody levels on human DBS has not been validated. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the use of human DBS for rabies serology and analyzed 99 pre- or post-vaccination serum and DBS samples with a fluorescent antibody virus neutralization test (FAVNt), which is the gold standard to detect protective antibody levels, and a Bio-Rad Platelia Rabies II ELISA. Sensitivity and specificity of DBS eluates tested with the FAVNt were 97% and 92%, respectively and 87% and 96% when tested with the Platelia-II ELISA. Antibody levels measured in serum with the FAVNt, correlated best with antibody levels measured in DBS with the FAVNt (R = 0.88). CONCLUSIONS/SIGNIFICANCE: This is the first study that applies DBS for reliable detection of human antibodies against rabies virus. Both the FAVNt and Platelia-II ELISA demonstrate an acceptable performance on DBS, providing opportunities for rabies serology in remote areas. This technique could drastically ease studies evaluating (novel) rabies vaccination strategies and monitoring persisting immunity in humans at risk, living in rabies endemic regions.

Genetic Features of HIV-1 Integrase Sub-Subtype A6 Predominant in Russia and Predicted Susceptibility to INSTIs.

The increasing use of the integrase strand transfer inhibitor (INSTI) class for the treatment of HIV-infection has pointed to the importance of analyzing the features of HIV-1 subtypes for an improved understanding of viral genetic variability in the occurrence of drug resistance (DR). In this study, we have described the prevalence of INSTI DR in a Russian cohort and the genetic features of HIV-1 integrase sub-subtype A6. We included 408 HIV infected patients who were not exposed to INSTI. Drug resistance mutations (DRMs) were detected among 1.3% of ART-naïve patients and among 2.7% of INSTI-naïve patients. The prevalence of 12 polymorphic mutations was significantly different between sub-subtypes A6 and A1. Analysis of the genetic barriers determined two positions in which subtype A (A1 and A6) showed a higher genetic barrier (G140C and V151I) compared with subtype B, and one position in which subtypes A1 and B displayed a higher genetic barrier (L74M and L74I) than sub-subtype A6. Additionally, we confirmed that the L74I mutation was selected at the early stage of the epidemic and subsequently spread as a founder effect in Russia. Our data have added to the overall understanding of the genetic features of sub-subtype A6 in the context of drug resistance.

Transmission of NS5A-Inhibitor Resistance-Associated Substitutions Among Men Who Have Sex With Men Recently Infected with Hepatitis C Virus Genotype 1a.

The transmission of direct-acting antiviral resistance-associated substitutions (RAS) could hamper hepatitis C virus (HCV) cure rates and elimination efforts. A phylogenetic analysis of 87 men who have sex with men recently infected with HCV genotype 1a placed one-third (28/87) in a large cluster, in which 96% harbored NS5A M28V RAS.

Distinct rates and patterns of spread of the major HIV-1 subtypes in Central and East Africa.

Since the ignition of the HIV-1 group M pandemic in the beginning of the 20th century, group M lineages have spread heterogeneously throughout the world. Subtype C spread rapidly through sub-Saharan Africa and is currently the dominant HIV lineage worldwide. Yet the epidemiological and evolutionary circumstances that contributed to its epidemiological expansion remain poorly understood. Here, we analyse 346 novel pol sequences from the DRC to compare the evolutionary dynamics of the main HIV-1 lineages, subtypes A1, C and D. Our results place the origins of subtype C in the 1950s in Mbuji-Mayi, the mining city of southern DRC, while subtypes A1 and D emerged in the capital city of Kinshasa, and subtypes H and J in the less accessible port city of Matadi. Following a 15-year period of local transmission in southern DRC, we find that subtype C spread at least three-fold faster than other subtypes circulating in Central and East Africa. In conclusion, our results shed light on the origins of HIV-1 main lineages and suggest that socio-historical rather than evolutionary factors may have determined the epidemiological fate of subtype C in sub-Saharan Africa.

Cost-effectiveness and budget effect of pre-exposure prophylaxis for HIV-1 prevention in Germany from 2018 to 2058.

BackgroundPre-exposure prophylaxis (PrEP) is a highly effective HIV prevention strategy for men-who-have-sex-with-men (MSM). The high cost of PrEP has until recently been a primary barrier to its use. In 2017, generic PrEP became available, reducing the costs by 90%.AimOur objective was to assess cost-effectiveness and costs of introducing PrEP in Germany.MethodsWe calibrated a deterministic mathematical model to the human immunodeficiency virus (HIV) epidemic among MSM in Germany. PrEP was targeted to 30% of high-risk MSM. It was assumed that PrEP reduces the risk of HIV infection by 85%. Costs were calculated from a healthcare payer perspective using a 40-year time horizon starting in 2018.ResultsPrEP can avert 21,000 infections (interquartile range (IQR): 16,000-27,000) in the short run (after 2 years scale-up and 10 years full implementation). HIV care is predicted to cost EUR 36.2 billion (IQR: 32.4-40.4 billion) over the coming 40 years. PrEP can increase costs by at most EUR 150 million within the first decade after introduction. Ten years after introduction, PrEP can become cost-saving, accumulating to savings of HIV-related costs of EUR 5.1 billion (IQR: 3.5-6.9 billion) after 40 years. In a sensitivity analysis, PrEP remained cost-saving even at a 70% price reduction of antiretroviral drug treatment and a lower effectiveness of PrEP.ConclusionIntroduction of PrEP in Germany is predicted to result in substantial health benefits because of reductions in HIV infections. Short-term financial investments in providing PrEP will result in substantial cost-savings in the long term.

Early treatment of acute hepatitis C infection is cost-effective in HIV-infected men-who-have-sex-with-men.

BACKGROUND: Treatment of hepatitis C virus infections (HCV) with direct acting antivirals (DAA) can prevent new infections since cured individuals cannot transmit HCV. However, as DAAs are expensive, many countries defer treatment to advances stages of fibrosis, which results in ongoing transmission. We assessed the epidemiological impact and cost-effectiveness of treatment initiation in different stages of infection in the Netherlands where the epidemic is mainly concentrated among HIV-infected MSMs. METHODS: We calibrated a deterministic mathematical model to the Dutch HCV epidemic among HIV-infected MSM to compare three different DAA treatment scenarios: 1) immediate treatment, 2) treatment delayed to chronic infection allowing spontaneous clearance to occur, 3) treatment delayed until F2 fibrosis stage. All scenarios are simulated from 2015 onwards. Total costs, quality adjusted life years (QALY), incremental cost-effectiveness ratios (ICERs), and epidemiological impact were calculated from a providers perspective over a lifetime horizon. We used a DAA price of €35,000 and 3% discounting rates for cost and QALYs. RESULTS: Immediate DAA treatment lowers the incidence from 1.2/100 person-years to 0.2/100 person-years (interquartile range 0.1-0.2) and the prevalence from 5.0/100 person-years to 0.5/100 person-years (0.4-0.6) after 20 years. Delayed treatment awaiting spontaneous clearance will result in a similar reduction. However, further delayed treatment to F2 will increases the incidence and prevalence. Earlier treatment will cost society €68.3 and €75.1 million over a lifetime for immediate and awaiting until the chronic stage, respectively. The cost will increase if treatment is further delayed until F2 to €98.4 million. Immediate treatment will prevent 7070 new infections and gains 3419 (3019-3854) QALYs compared to F2 treatment resulting in a cost saving ICER. Treatment in the chronic stage is however dominated. CONCLUSIONS: Early DAA treatment for HIV-infected MSM is an excellent and sustainable tool to meet the WHO goal of eliminating HCV in 2030.

Treatment of acute hepatitis C genotypes 1 and 4 with 8 weeks of grazoprevir plus elbasvir (DAHHS2): an open-label, multicentre, single-arm, phase 3b trial.

BACKGROUND: Direct-acting antivirals effectively treat chronic hepatitis C virus (HCV) infection but there is a paucity of data on their efficacy for acute HCV, when immediate treatment could prevent onward transmission. We assessed the efficacy of grazoprevir plus elbasvir treatment in acute HCV infection and investigated whether treatment can be shortened during the acute phase of HCV infection. METHODS: The Dutch Acute HCV in HIV study number 2 (DAHHS2) study was a single-arm, open-label, multicentre, phase 3b trial. Adult patients (≥18 years) with acute HCV genotype 1 or 4 infection (duration of infection 26 weeks or less, according to presumed day of infection) were recruited at 15 HIV outpatient clinics in the Netherlands and Belgium. All patients were treated with 8 weeks of grazoprevir 100 mg plus elbasvir 50 mg administered as one oral fixed drug combination tablet once daily. The primary efficacy endpoint was sustained virological response at 12 weeks after the end of treatment (SVR12; HCV RNA <15 IU/mL) in all patients who started treatment. Reinfection with a different HCV virus was not considered treatment failure in the primary analysis. This trial is registered with ClinicalTrials.gov, number NCT02600325. FINDINGS: Between Feb 15, 2016, and March 2, 2018, we assessed 146 patients with a recently acquired HCV infection for eligibility, of whom 86 were enrolled and 80 initiated therapy, all within 6 months after infection. All patients who initiated treatment completed treatment and no patients were lost to follow-up. 79 (99%, 95% CI 93-100) of 80 patients achieved SVR12. All 14 patients who were infected with a virus carrying a clinically significant polymorphism in NS5A were cured. If reinfections were considered treatment failures, 75 (94%, 86-98) of 80 patients achieved SVR12. Two serious adverse events not considered related to the treatment were reported (traumatic rectal bleeding and low back surgery). The most common adverse event was a new sexually transmitted infection (19 [24%] of 80 patients). The most common reported possibly drug-related adverse events were fatigue (11 [14%] patients), headache (seven [9%] patients), insomnia (seven [9%] patients), mood changes (five [6%] patients), dyspepsia (five [6%] patients), concentration impairment (four [5%] patients), and dizziness (4 [5%] patients), all of which were regarded as mild by the treating physician. No adverse events led to study drug discontinuation. INTERPRETATION: 8 weeks of grazoprevir plus elbasvir was highly effective for the treatment of acute HCV genotype 1 or 4 infection. The ability to treat acute HCV immediately after diagnosis might help physicians to reach the WHO goal of HCV elimination by 2030. FUNDING: Merck Sharp and Dohme and Health-Holland.

Impact and longevity of measles-associated immune suppression: a matched cohort study using data from the THIN general practice database in the UK.

OBJECTIVE: To test the hypothesis that measles infection increases the incidence of non-measles infectious diseases over a prolonged period of time. DESIGN: A population-based matched cohort study. DATA SOURCES: This study examined children aged 1-15 years in The Health Improvement Network UK general practice medical records database. Participants included 2228 patients diagnosed with measles between 1990 and 2014, which were matched on age, sex, general practitioner practice and calendar year with 19 930 children without measles. All controls had received at least one measles vaccination. Children with a history of immune-compromising conditions or with immune-suppressive treatment were excluded. PRIMARY OUTCOME MEASURES: Incidence rate ratio (IRR) of infections, anti-infective prescriptions and all-cause hospitalisations following measles in predetermined periods using multivariate analysis to adjust for confounding variables. RESULTS: In children with measles, the incidence rate for non-measles infectious disease was significantly increased in each time period assessed up to 5 years postmeasles: 43% in the first month (IRR: 1.43; 95% CI 1.22 to 1.68), 22% from month one to the first year (IRR: 1.22; 95% CI 1.14 to 1.31), 10% from year 1 to 2.5 years (IRR: 1.10; 95% CI 1.02 to 1.19) and 15% (IRR: 1.15; 95% CI 1.06 to 1.25) in years 2.5 to 5 years of follow-up. Children with measles were more than three times as likely to receive an anti-infective prescription in the first month and 15%-24% more likely between the first month and 5 years. The rate of hospitalisation in children with measles was increased only in the month following diagnosis but not thereafter (IRR: 2.83; 95% CI 1.72 to 4.67). CONCLUSION: Following measles, children had increased rates of diagnosed infections, requiring increased prescribing of antimicrobial therapies. This population-based matched cohort study supports the hypothesis that measles has a prolonged impact on host resistance to non-measles infectious diseases.

Zika virus and Guillain-Barré syndrome in Bangladesh.

OBJECTIVE: Previous studies have associated Guillain-Barré syndrome (GBS) with Zika virus (ZIKV) outbreaks in South America and Oceania. In Asia, ZIKV is known to circulate widely, but the association with Guillain-Barré syndrome is unclear. We investigated whether endemic ZIKV infection is associated with the development of GBS. METHODS: A prospective study was conducted from 2011 to 2015 in Bangladesh. A total of 418 patients and 418 healthy family controls were included in the study. Patients were diagnosed with GBS prior to inclusion according to established criteria. Detailed information on the epidemiology, clinical presentation, electrophysiology, diagnosis, disease severity, and clinical course were obtained during a follow-up of 1 year using a predefined protocol. RESULTS: ZIKV-neutralizing antibodies were detected in our study from 2013 onwards. The prevalence of ZIKV-neutralizing antibodies was not significantly higher in patients with GBS compared to healthy controls (OR 2.23, P = 0.14, 95% CI 0.77-6.53). Serological evidence for prior ZIKV infection in patients with GBS was associated with more frequent cranial, sensory, and autonomic nerve involvement compared to GBS patients with Campylobacter jejuni, the predominant preceding infection in GBS worldwide. Nerve-conduction studies revealed that ZIKV antibodies were associated with a demyelinating subtype of GBS, while C. jejuni infections were related to an axonal subtype. INTERPRETATION: No significant association was found between ZIKV infection and GBS in Bangladesh, but GBS following ZIKV infection was characterized by a distinct clinical and electrophysiological subtype compared to C. jejuni infection. These findings indicate that ZIKV may precede a specific GBS subtype but the risk is low.