Therapeutic strategies aimed at achieving antiretroviral therapy (ART)-free HIV remission in infected individuals are under active investigation. Considering the vast majority of HIV-infected ...individuals experience plasma viral rebound upon cessation of therapy, clinical trials evaluating the efficacy of curative strategies would likely require inclusion of ART interruption. However, it is unclear what impact short-term analytical treatment interruption (ATI) and subsequent reinitiation of ART have on immunologic and virologic parameters of HIV-infected individuals. Here, we show a significant increase of HIV burden in the CD4+ T cells of infected individuals during ATI that was correlated with the level of plasma viral rebound. However, the size of the HIV reservoirs as well as immune parameters, including markers of exhaustion and activation, returned to pre-ATI levels 6-12 months after the study participants resumed ART. Of note, the proportions of near full-length, genome-intact and structurally defective HIV proviral DNA sequences were similar prior to ATI and following reinitiation of ART. In addition, there was no evidence of emergence of antiretroviral drug resistance mutations within intact HIV proviral DNA sequences following reinitiation of ART. These data demonstrate that short-term ATI does not necessarily lead to expansion of the persistent HIV reservoir nor irreparable damages to the immune system in the peripheral blood, warranting the inclusion of ATI in future clinical trials evaluating curative strategies.
Background
Periprosthetic infection after total hip arthroplasty (THA) is a devastating complication. Reported rates of infection control range from 80% to 95% but mortality rates associated with ...treatment of infected THA are also substantial and we suspect underreported.
Questions/Purposes
For patients selected for two-stage treatment of infected THA we therefore determined (1) mortality; (2) rate of reimplantation; and (3) rate of reinfection.
Methods
We identified 202 patients (205 hips) with infected primary or revision THA treated with a two-stage protocol between 1996 and 2009 in our prospectively collected practice registry. Patients underwent two-stage treatment for infection, including removal of all implants and foreign material with implantation of an antibiotic-laden cement spacer in the first stage followed by intravenous culture-specific antibiotics for a minimum of 6 weeks. Second-stage reimplantation was performed if erythrocyte sedimentation rate and C-reactive protein were trending toward normal and the wound was well healed. Thirteen patients (13 hips) were lost to followup before 24 months. The minimum followup in surviving patients was 24 months or failure (average, 53 months; range, 24–180 months).
Results
Fourteen patients (7%; 14 hips) died before reimplantation and two were not candidates because of medical comorbidities. The 90-day mortality rate after the first-stage débridement was 4% (eight patients). Of the 186 patients (189 hips) who underwent reimplantation, 157 (83%) achieved control of the infection. Including all patients who underwent the first stage, survival and infection control after two-stage reimplantation was 76%.
Conclusion
Two-stage treatment of deep infection in primary and revision THA is associated with substantial mortality and a substantial failure rate from both reinfection and inability to perform the second stage.
Level of Evidence
Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV)
. However, eradication of the virus in individuals with HIV has not been possible to date
. Given that HIV ...suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication
. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.
HIV-1 infection remains a public health problem with no cure. Anti-retroviral therapy (ART) is effective but requires lifelong drug administration owing to a stable reservoir of latent proviruses ...integrated into the genome of CD4
T cells
. Immunotherapy with anti-HIV-1 antibodies has the potential to suppress infection and increase the rate of clearance of infected cells
. Here we report on a clinical study in which people living with HIV received seven doses of a combination of two broadly neutralizing antibodies over 20 weeks in the presence or absence of ART. Without pre-screening for antibody sensitivity, 76% (13 out of 17) of the volunteers maintained virologic suppression for at least 20 weeks off ART. Post hoc sensitivity analyses were not predictive of the time to viral rebound. Individuals in whom virus remained suppressed for more than 20 weeks showed rebound viraemia after one of the antibodies reached serum concentrations below 10 µg ml
. Two of the individuals who received all seven antibody doses maintained suppression after one year. Reservoir analysis performed after six months of antibody therapy revealed changes in the size and composition of the intact proviral reservoir. By contrast, there was no measurable decrease in the defective reservoir in the same individuals. These data suggest that antibody administration affects the HIV-1 reservoir, but additional larger and longer studies will be required to define the precise effect of antibody immunotherapy on the reservoir.
While qualitative assessments of Ebola virus disease (EVD)-related stigma have been undertaken among survivors and the general public, quantitative tools and assessment targeting survivors have been ...lacking.
Beginning in June 2015, EVD survivors from seven Liberian counties, where most of the country's EVD cases occurred, were eligible to enroll in a longitudinal cohort. Seven stigma questions were adapted from the People Living with HIV Stigma Index and asked to EVD survivors over the age of 12 at initial visit (median 358 days post-EVD) and 18 months later. Primary outcome was a 7-item EVD-related stigma index. Explanatory variables included age, gender, educational level, pregnancy status, post-EVD hospitalization, referred to medical care and EVD source. Proportional odds logistic regression models and generalized linear mixed-effects models were used to assess stigma at initial visit and over time. The stigma questions were administered to 859 EVD survivors at initial visit and 741 (86%) survivors at follow-up. While 63% of survivors reported any stigma at initial visit, only 5% reported any stigma at follow-up. Over the 18-month period, there was a significant decrease in stigma among EVD survivors (Adjusted Odds Ratio AOR, 0.02; 95% Confidence Interval CI, 0.01-0.04). At initial visit, having primary, junior high or vocational education, and being referred to medical care was associated with higher odds of stigma (educational level: AOR, 1.82; 95%CI, 1.27-2.62; referred: AOR, 1.50; 95%CI, 1.16-1.94). Compared to ages of 20-29, those who had ages of 12-19 or 50+ experienced lower odds of stigma (12-19: AOR, 0.32; 95%CI, 0.21-0.48; 50+: AOR, 0.58 95%CI, 0.37-0.91).
Our data suggest that EVD-related stigma was much lower more than a year after active Ebola transmission ended in Liberia. Among survivors who screened negative for stigma, additional probing may be considered based on age, education, and referral to care.
Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine ...safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy.
We performed a first in-human trial of Escherichia coli-produced rhIL-15. Bolus infusions of 3.0, 1.0, and 0.3 μg/kg per day of IL-15 were administered for 12 consecutive days to patients with metastatic malignant melanoma or metastatic renal cell cancer.
Flow cytometry of peripheral blood lymphocytes revealed dramatic efflux of NK and memory CD8 T cells from the circulating blood within minutes of IL-15 administration, followed by influx and hyperproliferation yielding 10-fold expansions of NK cells that ultimately returned to baseline. Up to 50-fold increases of serum levels of multiple inflammatory cytokines were observed. Dose-limiting toxicities observed in patients receiving 3.0 and 1.0 μg/kg per day were grade 3 hypotension, thrombocytopenia, and elevations of ALT and AST, resulting in 0.3 μg/kg per day being determined the maximum-tolerated dose. Indications of activity included clearance of lung lesions in two patients.
IL-15 could be safely administered to patients with metastatic malignancy. IL-15 administration markedly altered homeostasis of lymphocyte subsets in blood, with NK cells and γδ cells most dramatically affected, followed by CD8 memory T cells. To reduce toxicity and increase efficacy, alternative dosing strategies have been initiated, including continuous intravenous infusions and subcutaneous IL-15 administration.
Background
While short-stem design is not a new concept, interest has surged with increasing utilization of less invasive techniques. Short stems are easier to insert through small incisions. ...Reliable long-term results including functional improvement, pain relief, and implant survival have been reported with standard tapered stems, but will a short taper perform as well?
Questions/purposes
We compared short, flat-wedge, tapered, broach-only femoral stems to standard-length, double-tapered, ream and broach femoral stems in terms of intraoperative complications, short-term survivorship, and pain and function scores.
Patients and Methods
We retrospectively reviewed the records of 606 patients who had 658 THAs using a less invasive direct lateral approach from January 2006 to March 2008. Three hundred sixty patients (389 hips) had standard-length stems and 246 (269 hips) had short stems. Age averaged 63 years, and body mass index averaged 30.7 kg/m
2
. We recorded complications and pain and function scores and computed short-term survival. Minimum followup was 0.8 months (mean, 29.2 months; range, 0.8–62.2 months).
Results
We observed a higher rate of intraoperative complications with the standard-length stems (3.1%; three trochanteric avulsions, nine femoral fractures) compared with the shorter stems (0.4%; one femoral fracture) and managed all complications with application of one or more cerclage cables. There were no differences in implant survival, Harris hip score, and Lower Extremity Activity Scale score between groups.
Conclusions
Fewer intraoperative complications occurred with the short stems, attesting to the easier insertion of these devices. While longer followup is required, our early results suggest shortened stems can be used with low complication rates and do not compromise the survival and functional outcome of cementless THA.
Level of Evidence
Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
Detailed longitudinal studies of HIV-positive individuals in West Africa are lacking. Here the HIV prevalence, incidence, all-cause mortality, and the proportion of individuals receiving treatment ...with cART in two cohorts of participants in Ebola-related studies are described.
Individuals of all ages were enrolled and followed at four sites in the area of Monrovia, Liberia.
Two cohorts identified in response to the Ebola epidemic are described to provide insights into the current state of the HIV epidemic. HIV testing was performed at baseline for participants in both cohorts and during follow-up in one cohort.
Prevalence and incidence of HIV (prevalence of 3.1% for women and 1.4% for men and incidence of 3.3 per 1,000) were higher in these cohorts compared to 2018 national estimates (prevalence of 1.3% and incidence of 0.39 per 1,000). Most participants testing positive did not know their status prior to testing. Of those who knew they were HIV positive, 7.9% reported being on antiretroviral treatment. The death rate among those with HIV was 12.3% compared to 1.9% in HIV-negative individuals (adjusted odds ratio of 6.87). While higher levels of d-dimer were associated with increased mortality, this was not specific to those with HIV, however lower hemoglobin levels were associated with increased mortality among those with HIV.
These findings point to a need to perform further research studies aimed at fulfilling these knowledge gaps and address current shortcomings in the provision of care for those living with HIV in Liberia.
A Longitudinal Study of Ebola Sequelae in Liberia Sneller, Michael C; Reilly, Cavan; Badio, Moses ...
New England journal of medicine/The New England journal of medicine,
03/2019, Volume:
380, Issue:
10
Journal Article
Peer reviewed
Open access
Multiple health problems have been reported in survivors of Ebola virus disease (EVD). Attribution of these problems to the disease without a control group for analysis is difficult.
We enrolled a ...cohort of EVD survivors and their close contacts and prospectively collected data on symptoms, physical examination findings, and laboratory results. A subset of participants underwent ophthalmologic examinations. Persistence of Ebola virus (EBOV) RNA in semen samples from survivors was determined.
A total of 966 EBOV antibody-positive survivors and 2350 antibody-negative close contacts (controls) were enrolled, and 90% of these participants were followed for 12 months. At enrollment (median time to baseline visit, 358 days after symptom onset), six symptoms were reported significantly more often among survivors than among controls: urinary frequency (14.7% vs. 3.4%), headache (47.6% vs. 35.6%), fatigue (18.4% vs. 6.3%), muscle pain (23.1% vs. 10.1%), memory loss (29.2% vs. 4.8%), and joint pain (47.5% vs. 17.5%). On examination, more survivors than controls had abnormal abdominal, chest, neurologic, and musculoskeletal findings and uveitis. Other than uveitis (prevalence at enrollment, 26.4% vs. 12.1%; at year 1, 33.3% vs. 15.4%), the prevalence of these conditions declined during follow-up in both groups. The incidence of most symptoms, neurologic findings, and uveitis was greater among survivors than among controls. EBOV RNA was detected in semen samples from 30% of the survivors tested, with a maximum time from illness to detection of 40 months.
A relatively high burden of symptoms was seen in all participants, but certain symptoms and examination findings were more common among survivors. With the exception of uveitis, these conditions declined in prevalence during follow-up in both groups. Viral RNA in semen persisted for a maximum of 40 months. (Funded by the National Institute of Allergy and Infectious Diseases and the National Eye Institute; PREVAIL III ClinicalTrials.gov number, NCT02431923.).
Antibody titers against a viral pathogen are typically measured using an antigen binding assay, such as an enzyme-linked immunosorbent assay (ELISA), which only measures the ability of antibodies to ...identify a viral antigen of interest. Neutralization assays measure the presence of virus-neutralizing antibodies in a sample. Traditional neutralization assays, such as the plaque reduction neutralization test (PRNT), are often difficult to use on a large scale due to being both labor and resource intensive. Here we describe an Ebola virus fluorescence reduction neutralization assay (FRNA), which tests for neutralizing antibodies, that requires only a small volume of sample in a 96-well format and is easy to automate. The readout of the FRNA is the percentage of Ebola virus-infected cells measured with an optical reader or overall chemiluminescence that can be generated by multiple reading platforms. Using blinded human clinical samples (EVD survivors or contacts) obtained in Liberia during the 2013-2016 Ebola virus disease outbreak, we demonstrate there was a high degree of agreement between the FRNA-measured antibody titers and the Filovirus Animal Non-clinical Group (FANG) ELISA titers with the FRNA providing information on the neutralizing capabilities of the antibodies.
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