Long-term neurological and neurocognitive impairments after tick-borne encephalitis in Lithuania - a prospective study.

BACKGROUND: The aim of this study was to characterise long-term neurological and neurocognitive sequelae after tick-borne encephalitis (TBE) in adults. METHODS: 98 prospective consecutive TBE patients, classified by disease severity, were included. Immediate outcomes were evaluated with Glasgow Outcome Scale (GOS) and Rankin Scale (RS). After 6 and 18 months, long-term disability was evaluated using Modified Rankin Scale (MRS) and neurocognitive assessment was performed with Matrics Consensus Cognitive Battery (MCCB), measuring processing speed, attention/vigilance, working memory, verbal learning, visual learning, reasoning/problem solving and social cognition. The MCCB results were compared to healthy age, gender and education-matched controls. RESULTS: Mild, moderate, and severe TBE was diagnosed in 53.1%, 38.8%, and 8.2% of cases, respectively. At discharge, 25.5% of the patients had major or moderate impairments (GOS) and various levels of disability in 34.7% (RS). Up to 18 months from the onset of TBE, over 20% remained with slight to moderate disability (MRS). GOS, RS and MRS scores correlated with disease severity. At 6 months after the onset, TBE patients scored significantly lower than controls in processing speed, verbal, and visual learning. Two latter domains were significantly more impaired in patients with mild TBE. Patients aged 18-39 performed significantly worse in attention/vigilance and working memory, whereas aged 60+ in verbal learning. A year later, significant improvement was observed in six of seven cognitive domains. CONCLUSIONS: Long-term neurological sequelae persist in a substantial proportion of TBE patients with significant impairment in several cognitive domains, especially in younger patients and even after mild TBE.

Serum and cerebrospinal fluid brain damage markers neurofilament light and glial fibrillary acidic protein correlate with tick-borne encephalitis disease severity-a multicentre study on Lithuanian and Swedish patients.

BACKGROUND AND PURPOSE: Our aim was to examine the correlation between biomarkers of neuronal and glial cell damage and severity of disease in patients with tick-borne encephalitis. METHODS: One hundred and fifteen patients with tick-borne encephalitis diagnosed in Lithuania and Sweden were prospectively included, and cerebrospinal fluid (CSF) and serum samples were obtained shortly after hospitalization. Using pre-defined criteria, cases were classified as mild, moderate or severe tick-borne encephalitis. Additionally, the presence of spinal nerve paralysis (myelitis) and/or cranial nerve affection were noted. Concentrations of the brain cell biomarkers glial fibrillary acidic protein (GFAP), YKL-40, S100B, neurogranin, neurofilament light (NfL) and tau were analysed in CSF and, in addition, NfL, GFAP and S100B levels were measured in serum. The Jonckheere-Terpstra test was used for group comparisons of continuous variables and Spearman's partial correlation test was used to adjust for age. RESULTS: Cerebrospinal fluid and serum concentrations of GFAP and NfL correlated with disease severity, independent of age, and with the presence of nerve paralysis. The markers neurogranin, YKL-40, tau and S100B in CSF and S100B in serum were detected, but their concentrations did not correlate with disease severity. CONCLUSIONS: Neuronal cell damage and astroglial cell activation with increased NfL and GFAP in CSF and serum were associated with a more severe disease, independent of age. Increased GFAP and NfL concentrations in CSF and NfL in serum were also indicative of spinal and/or cranial nerve damage. NfL and GFAP are promising prognostic biomarkers in tick-borne encephalitis, and future studies should focus on determining the association between these biomarkers and long-term sequelae.

Safety and immunogenicity following co-administration of Yellow fever vaccine with Tick-borne encephalitis or Japanese encephalitis vaccines: Results from an open label, non-randomized clinical trial.

BACKGROUND: Flavivirus infections pose a significant global health burden underscoring the need for the development of safe and effective vaccination strategies. Available flavivirus vaccines are from time to time concomitantly delivered to individuals. Co-administration of different vaccines saves time and visits to health care units and vaccine clinics. It serves to provide protection against multiple pathogens in a shorter time-span; e.g., for individuals travelling to different endemic areas. However, safety and immunogenicity-related responses have not been appropriately evaluated upon concomitant delivery of these vaccines. Therefore, we performed an open label, non-randomized clinical trial studying the safety and immunogenicity following concomitant delivery of the yellow fever virus (YFV) vaccine with tick-borne encephalitis virus (TBEV) and Japanese encephalitis virus (JE) virus vaccines. METHODS AND FINDINGS: Following screening, healthy study participants were enrolled into different cohorts receiving either TBEV and YFV vaccines, JEV and YFV vaccines, or in control groups receiving only the TBEV, JEV, or YFV vaccine. Concomitant delivery was given in the same or different upper arms for comparison in the co-vaccination cohorts. Adverse effects were recorded throughout the study period and blood samples were taken before and at multiple time-points following vaccination to evaluate immunological responses to the vaccines. Adverse events were predominantly mild in the study groups. Four serious adverse events (SAE) were reported, none of them deemed related to vaccination. The development of neutralizing antibodies (nAbs) against TBEV, JEV, or YFV was not affected by the concomitant vaccination strategy. Concomitant vaccination in the same or different upper arms did not significantly affect safety or immunogenicity-related outcomes. Exploratory studies on immunological effects were additionally performed and included studies of lymphocyte activation, correlates associated with germinal center activation, and plasmablast expansion. CONCLUSIONS: Inactivated TBEV or JEV vaccines can be co-administered with the live attenuated YFV vaccine without an increased risk of adverse events and without reduced development of nAbs to the respective viruses. The vaccines can be delivered in the same upper arm without negative outcome. In a broader perspective, the results add valuable information for simultaneous administration of live and inactivated flavivirus vaccines in general. TRIAL REGISTRATION: Eudra CT 2017-002137-32.

Recommendations to Improve Tick-Borne Encephalitis Surveillance and Vaccine Uptake in Europe.

There has been an increase in reported TBE cases in Europe since 2015, reaching a peak in some countries in 2020, highlighting the need for better management of TBE risk in Europe. TBE surveillance is currently limited, in part, due to varying diagnostic guidelines, access to testing, and awareness of TBE. Consequently, TBE prevalence is underestimated and vaccination recommendations inadequate. TBE vaccine uptake is unsatisfactory in many TBE-endemic European countries. This review summarizes the findings of a scientific workshop of experts to improve TBE surveillance and vaccine uptake in Europe. Strategies to improve TBE surveillance and vaccine uptake should focus on: aligning diagnostic criteria and testing across Europe; expanding current vaccine recommendations and reducing their complexity; and increasing public education of the potential risks posed by TBEV infection.

Picornavirus May Be Linked to Parkinson's Disease through Viral Antigen in Dopamine-Containing Neurons of Substantia Nigra.

Parkinson's disease (PD) is a neurodegenerative disease linked with the loss of dopaminergic neurons in the brain region called substantia nigra and caused by unknown pathogenic mechanisms. Two currently recognized prominent features of PD are an inflammatory response manifested by glial reaction and T-cell infiltration, as well as the presence of various toxic mediators derived from activated glial cells. PD or parkinsonism has been described after infection with several different viruses and it has therefore been hypothesized that a viral infection might play a role in the pathogenesis of the disease. We investigated formalin-fixed post-mortem brain tissue from 9 patients with Parkinson's disease and 11 controls for the presence of Ljungan virus (LV) antigen using a polyclonal antibody against the capsid protein of this recently identified picornavirus with neurotropic properties, suspected of being both a human and an animal pathogen. Evidence of viral antigen was found in 7 out of 9 Parkinson's disease cases and in only 1 out of 11 controls (p = 0.005). The picornavirus antigen was present in dopamine-containing neurons of the substantia nigra. We propose that LV or an LV-related virus initiates the pathological process underlying sporadic PD. LV-related picornavirus antigen has also been reported in patients with Alzheimer's disease. Potentially successful antiviral treatment in Alzheimer's disease suggests a similar treatment for Parkinson's disease. Amantadine, originally developed as an antiviral drug against influenza infection, has also been used for symptomatic treatment of patients with PD for more than 50 years and is still commonly used by neurologists today. The fact that amantadine also has an antiviral effect on picornaviruses opens the question of this drug being re-evaluated as potential PD therapy in combination with other antiviral compounds directed against picornaviruses.

Three-dose versus four-dose primary schedules for tick-borne encephalitis (TBE) vaccine FSME-immun for those aged 50 years or older: A single-centre, open-label, randomized controlled trial.

BACKGROUND: TBE vaccination failures among those past middle age have raised concern about immune response declining with age. We investigated immunogenicity of the TBE-vaccine FSME-Immun among those aged 50+ years using the standard three-dose primary series and alternative four-dose schedules. METHODS: In this single-centre, open-label, randomized controlled trial, 200 TBE-naive Swedish adults were given primary TBE vaccination with FSME-Immun. Those aged 50+ years (n = 150) were randomized to receive the standard three-dose (days 0-30-360) or one of two four-dose series (0-7-21-360; 0-30-90-360). For participants < 50 years (n = 50) the standard three-dose schedule was used. Titres of neutralizing antibodies were determined on days 0, 60, 120, 360, and 400. The main outcome was the log titre of TBE virus-specific neutralizing antibodies on day 400. RESULTS: The three-dose schedule yielded lower antibody titres among those aged 50+ years than the younger participants on day 400 (geometric mean titre 41 versus 74, p < 0.05). The older group showed higher titres for the four-dose 0-7-21-360 than the standard three-dose schedule both on day 400 (103 versus 41, p < 0.01; primary end point) and at the other testing points (days 60, 120, 360). Using the other four-dose schedule (0-30-90-360), no such difference was observed on day 400 (63 versus 41, NS). CONCLUSION: Immune response to the TBE vaccine declined with age. A four-dose schedule (0-7-21-360) may benefit those aged 50 years or older. This study is registered at ClinicalTrials.gov, NCT01361776.

Potential Virus Involvement in Alzheimer's Disease: Results from a Phase IIa Trial Evaluating Apovir, an Antiviral Drug Combination.

BACKGROUND: Accumulating data suggest infectious agents are involved in Alzheimer's disease (AD). The two primary aims of this trial were to assess safety and efficacy of an antiviral drug combination on AD progression. OBJECTIVE: The trial evaluated whether Apovir, a combination of two antiviral agents, pleconaril (active on enteroviruses) and ribavirin (active on several viruses), could slow AD progression. METHODS: Sixty-nine patients 60-85 years were treated with Apovir or placebo for 9 months and followed until 12 months after end of treatment. Cognitive tests, safety, biomarkers, drug plasma, and cerebrospinal fluid concentrations were assessed. RESULTS: The tolerability of Apovir was compromised as demonstrated by the large drop-out rate and increased frequency and severity of adverse events. The primary endpoint, demonstrating a difference in change from baseline to 9 months between groups in ADAS-cog total score, was not met (p = 0.1809). However, there were observations indicating potential effects on both ADAS-cog and CDR-SB but these effects need to be verified. Also, there was a decrease in cerebrospinal fluid amyloid-ß in Apovir at 9 months (p = 0.0330) but no change in placebo. CONCLUSION: This was the first randomized, placebo controlled clinical trial exploring antiviral treatment on AD progression. The trial is considered inconclusive due to the large drop-out rate. New trials are needed to verify if the indications of effect observed can be confirmed and which component(s) in Apovir contributed to such effects. Pleconaril alone may be studied to improve the tolerability and to verify if enterovirus is involved in the disease process.

Effectiveness of Antivirals in a Type 1 Diabetes Model and the Move Toward Human Trials.

A Picornavirus (Ljungan virus [LV]) originally found in bank voles has been associated with type 1 diabetes (T1D) in its wild rodent reservoir, but also associated with T1D in a laboratory rat model for the disease, the diabetes prone (DP) Bio Breeding (BB) rat. Successful treatment of diabetes in this rat model, using experimental antiviral compounds directed against picornavirus, has been reported. In the present study we show significant clinical response in DP-BB rats using antiviral compounds available for human use (Pleconaril, Efavirenz, and Ribavirin). Presence of LV picornavirus antigen has been detected in islets of Langerhans from both human and the T1D rat model with clear morphological similarity. Based on these data it would be of interest to test antiviral treatment in patients with newly diagnosed T1D. Successful outcome will offer both proof of concept regarding the role of virus involvement in the disease and possibly a first generation treatment interrupting a persistent infection and stopping ß-cell destruction.

Picornavirus Identified in Alzheimer's Disease Brains: A Pathogenic Path?

We investigated formalin-fixed postmortem brain tissue from the hippocampus region of 18 AD cases and 11 age-matched controls using a polyclonal antibody against Ljungan virus (LV) capsid protein 1. Evidence of a LV antigen was found in all AD cases but in none of the control specimens (p < 0.0001). The antibodies reacted with neurons and astrocytes and also showed distinct positive reaction in the amyloid/neuritic plaques. The possible role of an incompletely characterized picornavirus as the etiologic agent in AD open up the possibility of treatment with antiviral therapy directed against picornaviruses. The positive result of such treatment in a small number of patients is presented separately back to back to this report.

Magnitude and Functional Profile of the Human CD4+ T Cell Response throughout Primary Immunization with Tick-Borne Encephalitis Virus Vaccine.

Tick-borne encephalitis (TBE) is a viral infection of the CNS caused by TBE virus. With no specific treatment available, the only protection is a formalin-inactivated whole virus vaccine. Primary immunization with European TBE vaccines, as recommended by the manufacturers, consists of three vaccine doses administered within a 1-y period. Protection from vaccination is believed to be mediated by Abs, yet T cells may also have a protective role. We set out to characterize the human CD4+ T cell response throughout primary TBE immunization. The responses were evaluated before vaccination and 1 mo after each vaccine dose. A heterogeneous magnitude of CD4+ T cell-mediated memory responses was observed in regard to lymphoblast expansion and cytokine production (IFN-γ, IL-2, and TNF), with the highest median magnitude detected after the second dose of vaccine. Stimulation with an overlapping peptide library based on structural TBE virus proteins E and C revealed that CD4+ T cells concomitantly producing IL-2 and TNF dominated the responses from vaccinees after each vaccine dose, whereas a control cohort of TBE patients responded mainly with all three cytokines. CD107a expression was not upregulated upon peptide stimulation in the vaccinees. However, CD154 (CD40L) expression on cytokine-positive memory CD4+ T cells significantly increased after the second vaccine dose. Taken together, TBE vaccination induced CD4+ T cell responses dominated by IL-2 and TNF production together with CD154 upregulation and a lower IFN-γ response compared with TBE patients. This response pattern was consistent after all three doses of TBE vaccine.

Tick-borne Encephalitis Vaccine Failures: A 10-year Retrospective Study Supporting the Rationale for Adding an Extra Priming Dose in Individuals Starting at Age 50 Years.

BACKGROUND: Southern Sweden is endemic for tick-borne encephalitis (TBE), with Stockholm County as one of the high-risk areas. Our aim in this study was to describe cases of vaccine failures and to optimize future vaccination recommendations. METHODS: Patients with TBE were identified in the notification database at the Department of Communicable Disease Control and Prevention in Stockholm County during 2006-2015. Vaccine failure was defined as TBE despite adherence to the recommended vaccination schedule with at least 2 doses. Clinical data were extracted from medical records. RESULTS: A total of 1004 TBE cases were identified, 53 (5%) were defined as vaccine failures. In this latter group, the median age was 62 years (6-83). Forty-three (81%) patients were aged >50 years and 2 were children. Approximately half of the patients had comorbidities, with diseases affecting the immune system accounting for 26% of all cases. Vaccine failures following the third or fourth vaccine dose accounted for 36 (68%) of the patients. Severe and moderate TBE disease affected 81% of the cases. CONCLUSIONS: To our knowledge, this is the largest documented cohort of TBE vaccine failures. Vaccine failure after 5 TBE vaccine doses is rare. Our data provide rationale for adding an extra priming dose to those aged ≥50 years.

Cell-Mediated Immune Responses and Immunopathogenesis of Human Tick-Borne Encephalitis Virus-Infection.

Tick-borne encephalitis virus (TBEV) is a flavivirus that belongs to the Flaviviridae family. TBEV is transmitted to humans primarily from infected ticks. The virus causes tick-borne encephalitis (TBE), an acute viral disease that affects the central nervous system (CNS). Infection can lead to acute neurological symptoms of significant severity due to meningitis or meningo(myelo)encephalitis. TBE can cause long-term suffering and has been recognized as an increasing public health problem. TBEV-affected areas currently include large parts of central and northern Europe as well as northern Asia. Infection with TBEV triggers a humoral as well as a cell-mediated immune response. In contrast to the well-characterized humoral antibody-mediated response, the cell-mediated immune responses elicited to natural TBEV-infection have been poorly characterized until recently. Here, we review recent progress in our understanding of the cell-mediated immune response to human TBEV-infection. A particular emphasis is devoted to studies of the response mediated by natural killer (NK) cells and CD8 T cells. The studies described include results revealing the temporal dynamics of the T cell- as well as NK cell-responses in relation to disease state and functional characterization of these cells. Additionally, we discuss specific immunopathological aspects of TBEV-infection in the CNS.

Incidence of tuberculosis and the need of prophylactic treatment in persons living with HIV in Stockholm during the era of anti-retroviral therapy 1996-2013.

BACKGROUND: The aim of this observational cohort study was to determine the incidence and risk factors of active tuberculosis (TB) in persons living with HIV in a low endemic setting over a 17-year time period when combination antiretroviral therapy (ART) has been available. We thereby aimed to understand the usefulness of TB chemoprophylaxis among HIV patients with latent TB. METHODS: All 2127 adult patients diagnosed with HIV January 1996-December 2013 at the Karolinska University Hospital in Stockholm County were eligible. After exclusion of 259 patients transferred to other clinics, 1868 were followed until TB diagnosis, death or end of study period (December 2013). The median follow-up time was 7.9 years (interquartile range, 3.9-11.5). RESULTS: Active TB was diagnosed in 92 patients, corresponding to an incidence rate of 6.2 cases (95% CI 5.1-7.6) per 1000 person-years with a significant decline over time. The majority (52%) of TB cases were diagnosed within 1 month from HIV diagnosis. Being a migrant from a TB-endemic region, was the only patient characteristic associated with significantly higher risk of active TB (Hazard Ration, HR: 8.54, 95% confidence interval, CI: 3.09-23.61 in a multivariate regression analysis controlling for route of HIV transmission, year of HIV diagnosis and CD4-cell count and viral load at HIV diagnosis. The number needed to treat to prevent one case of TB among patients in this high-risk group was 22 (95% CI 26-47). CONCLUSION: The incidence of active TB in persons living with HIV in Stockholm County declined significantly after the introduction of ART but was still 80 times higher than in the general population at the end of the study period. The therapeutic gain of chemoprophylaxis in low endemic settings should be weighed against costs and side effects.

Recent and historical trends in the epidemiology of Japanese encephalitis and its implication for risk assessment in travellers.

Japanese encephalitis is a major disease in many countries in Asia often visited by both leisure and non-leisure travellers. Although reported cases of Japanese apoptosis (JE) in travellers are relatively few, there are indications that both the number of cases might be underreported and that changes in the epidemiological situation in these parts of Asia may increase the risk, especially non-leisure travellers. Although JE mainly is considered a rural disease urban cases are seen the large economic growth and urbanization of previously rural areas in many for JE high-endemic areas may further add to the risk for JE, especially for business travellers, when visiting newly established peri-urban areas. This review will address these dynamic and unpredictable risks for JE and discuss its possible implications for the traveller.

Breadth and Dynamics of HLA-A2- and HLA-B7-Restricted CD8+ T Cell Responses against Nonstructural Viral Proteins in Acute Human Tick-Borne Encephalitis Virus Infection.

Tick-borne encephalitis virus (TBEV) is a leading cause of viral meningoencephalitis in many parts of Europe and eastwards in Asia, with high morbidity and often long-term neurologic sequelae. With no treatment available, studies of the immune response to TBEV are essential for the understanding of the immunopathogenesis of tick-borne encephalitis and for the development of therapeutics. We have previously demonstrated that CD8+ T cell responses in peripheral blood in patients with acute TBEV peak at around 7 d after hospitalization in the neuroinvasive phase of the disease. In this study, we identified six novel TBEV HLA-A2- and HLA-B7-restricted epitopes, all derived from the nonstructural proteins of TBEV. This identification allowed for a comprehensive phenotypic and temporal analysis of the HLA-A2- and HLA-B7-restricted Ag-specific CD8+ T cell response during the acute stages of human TBEV infection. HLA-A2- and HLA-B7-restricted TBEV epitope-specific effector cells predominantly displayed a CD45RA-CCR7-CD27+CD57- phenotype at day 7, which transitioned into separate distinct phenotypes for HLA-A2- and HLA-B7-restricted TBEV-specific CD8+ T cells, respectively. At day 21, the most prevalent phenotype in the HLA-A2-restricted CD8+ T cell populations was CD45RA-CCR7-CD27+CD57+, whereas the HLA-B7-restricted CD8+ T cell population was predominantly CD45RA+CCR7-CD27+CD57+ Almost all TBEV epitope-specific CD8+ T cells expressed α4 and ß1 integrins at days 7 and 21, whereas the bulk CD8+ T cells expressed lower integrin levels. Taken together, human TBEV infection elicits broad responses to multiple epitopes, predominantly derived from the nonstructural part of the virus, establishing distinct maturation patterns for HLA-A2- and HLA-B7-restricted TBEV epitope-specific CD8+ T cells.

The burden of chickenpox disease in Sweden.

BACKGROUND: Chickenpox vaccine is not included in the routine childhood vaccination programme in Sweden. The aim of this study was to estimate the baseline of national chickenpox disease burden, as comprehensive studies, required for an assessment regarding vaccine introduction, are lacking. METHODS: We used available health care registers and databases; the death register, hospitalisations register, communicable disease notifications database, Stockholm County registers on consultations in specialist and primary care, temporary parental benefit to care for a sick child, and searches on the health care system's website. From each data source, records regarding chickenpox were identified and extracted, either using relevant diagnosis codes (ICD-10) or key words. A descriptive analysis with regards to number of cases and incidence, severity, and seasonality, was carried out covering the time period 2007 to 2013. RESULTS: There were on average 333 patients hospitalised annually due to chickenpox, yielding a hospitalisation rate of 3.56/100,000 person-years. We found a slight male predominance in hospitalised cases. The highest hospitalisation rate was seen in 1 year-olds, whereas the peak in primary care consultations was in 2 year-olds. Nearly a quarter of children had parents who reported absence from work to care for them when sick with chickenpox. The average yearly death rate from chickenpox was 0.034/100,000 person-years. The duration of hospital stay increased with age. The seasonality in number of searches on the health care website corresponded well with hospitalisations and primary care consultations with peaks in spring. CONCLUSIONS: This study shows chickenpox death and hospitalisation rates in range with other European countries without routine vaccination. Swedish children fall ill with chickenpox at a very young age. The study provides essential input for future discussions on the introduction of routine chickenpox vaccination in Sweden.

NK Cell Responses to Human Tick-Borne Encephalitis Virus Infection.

Tick-borne encephalitis virus (TBEV) is a flavivirus that is transferred to humans by infected ticks. The virus causes tick-borne encephalitis, a severe infection of the CNS with a high risk for long-lasting sequelae. Currently, no treatment exists for the disease. Understanding the cellular immune response to this infection is important to gain further understanding into the pathogenesis, treatment, and prevention of the disease. NK cells are known to participate in the control of viral infections. We performed a longitudinal analysis of the human NK cell response to TBEV infection in a cohort of infected individuals from the onset of severe clinical symptoms to the convalescence phase. NK cell activation, as measured by expression of Ki67, was apparent at the time of hospitalization. By 3 wk after hospitalization, it decreased to levels seen in healthy controls. Concomitant with the increase in NK cell activation, augmented levels of IL-12, IL-15, IL-18, IFN-γ, and TNF were detected in patient plasma. This TBEV-induced NK cell activation was restricted predominantly to differentiated CD57(+)CD56(dim) NK cells. Functionally, CD56(dim) NK cells responded poorly to target cells at the time of hospitalization, but they recovered functional capacity to control levels during the convalescent phase. In contrast, the responsiveness of NK cells to cytokine stimulation remained intact throughout the disease. These findings demonstrate that NK cells respond to TBEV infection with characteristics that are distinct from those of other human viral infections and provide insights into the NK cell response to clinical TBEV infection.

Phylogenetic Analysis of Ethiopian HIV-1 Subtype C Near Full-Length Genomes Reveals High Intrasubtype Diversity and a Strong Geographical Cluster.

In this study, we characterize HIV-1 subtype C (HIV-1C) strains at the near full-length genome (NFLG) level and perform genotypic drug resistance testing (GRT) and genotypic tropism testing (GTT) from Ethiopia (HIV-1CET). Plasma samples (n = 150) were obtained from therapy-naive individuals residing in Addis Ababa, Ethiopia in 2008. HIV-NFLG was performed in a subset of patients (n = 30). GRT (pol) and GTT (V3 env) were performed using in-house methods. GTT was analyzed by PhenoSeq-C. The phylogenetic analysis of the NLFG identified two separate clusters of HIV-1CET, although all strains formed one large overarching cluster together. At NFLG, greater diversity was found among HIV-1CET strains compared to HIV-1C strains from other geographical locations. The geographic clustering was weak in the small subgenomic (pol and env) regions. The primary drug-resistant mutations were identified at a low level (<5%). GTT identified that 12% (12/102) of the patients were predicted to be harboring X4-tropic or both R5/X4-tropic viruses.

Efficacy and Safety of Antiretroviral Therapy Initiated One Week after Tuberculosis Therapy in Patients with CD4 Counts < 200 Cells/µL: TB-HAART Study, a Randomized Clinical Trial.

BACKGROUND: Given the high death rate the first two months of tuberculosis (TB) therapy in HIV patients, it is critical defining the optimal time to initiate combination antiretroviral therapy (cART). METHODS: A randomized, open-label, clinical trial comparing efficacy and safety of efavirenz-based cART initiated one week, four weeks, and eight weeks after TB therapy in patients with baseline CD4 count < 200 cells/µL was conducted. The primary endpoint was all-cause mortality rate at 48 weeks. The secondary endpoints were hepatotoxicity-requiring interruption of TB therapy, TB-associated immune reconstitution inflammatory syndrome, new AIDS defining illnesses, CD4 counts, HIV RNA levels, and AFB smear conversion rates. All analyses were intention-to-treat. RESULTS: We studied 478 patients with median CD4 count of 73 cells/µL and 5.2 logs HIV RNA randomized to week one (n = 163), week four (n = 160), and week eight (n = 155). Sixty-four deaths (13.4%) occurred in 339.2 person-years. All-cause mortality rates at 48 weeks were 25 per 100 person-years in week one, 18 per 100 person-years in week four and 15 per 100 person-years in week eight (P = 0.2 by the log-rank test). All-cause mortality incidence rate ratios in subgroups with CD4 count below 50 cells/µL versus above were 2.8 in week one (95% CI 1.2-6.7), 3.1 in week four (95% CI 1.2-8.6) and 5.1 in week eight (95% CI 1.8-16). Serum albumin < 3 gms/dL (adjusted HR, aHR = 2.3) and CD4 < 50 cells/µL (aHR = 2.7) were independent predictors of mortality. Compared with similar subgroups from weeks four and eight, first-line TB treatment interruption was high in week one deaths (P = 0.03) and in the CD4 subgroup <50 cells/µL (P = 0.02). CONCLUSIONS: Antiretroviral therapy one week after TB therapy doesn't improve overall survival. Despite increased mortality with CD4 < 50 cells/µL, we recommend cART later than the first week of TB therapy to avoid serious hepatotoxicity and treatment interruption. TRIAL REGISTRATION: ClinicalTrials.gov NCT 01315301.