Is the level of varicella-zoster virus IgG associated with symptomatic status of genital herpes simplex virus infection? A case-control study.

BACKGROUND: Herpes simplex virus (HSV) is a common infection, affecting the majority of the population by age of 50. Recurrent symptomatic outbreaks, experienced by a minority, have significant psychological and psychosexual effects. The varicella zoster virus (VZV), resembling HSV, shows potential for a functional cure via vaccination. This study seeks to investigate if there is an association between low VZV antibody levels and recurrent HSV outbreaks. METHODS: A total of 110 patients with symptomatic and asymptomatic HSV were recruited during their sexual health screen. Serum samples were collected between Aug 2019 - July 2022; breaks in the study occurred due to COVID. The primary outcome measure was the serological status of HSV and VZV IgG titre level. RESULTS: The average age was 37.3 years (range 21-65 years). For people with asymptomatic genital HSV2 the average VZV IgG titre was 2373.9 IU/mL (n = 17); and 1219.0 IU/mL for the symptomatic group (n = 67); p ≤ 0.00001), with similar results for HSV1. CONCLUSION: There is a strong association between average higher varicella-zoster virus (VZV) IgG level and being an asymptomatic carrier of herpes simplex sirus (HSV)1&2. A feasibility study to assess the use of the VZV vaccine as a treatment of HSV is planned.

Comparing lateral flow testing with a rapid RT-PCR method for SARS-CoV-2 detection in the United Kingdom-A retrospective diagnostic accuracy study.

Background and Aims: In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China. Rapid global spread led to the coronavirus disease 2019 (Covid-19) pandemic. Accurate detection of SARS-CoV-2 has become a vitally important tool in controlling the spread of the virus. Lateral flow devices (LFDs) offer the potential advantage of speed and on-site testing. The sensitivity of these devices compared to reverse transcription-polymerase chain reaction (RT-PCR) has been questioned. Methods: We compared the sensitivity of the Innova LFD, used widely in the United Kingdom, with our rapid RT-PCR method using stored positive samples. Samples with a range of viral loads (original Ct values 18.9-36.5) were tested. Results: The Innova LFD was found to be 6000-10,000 times less sensitive than RT-PCR for SARS-CoV-2 detection. Overall, the LFD detected 46.2% of the positives detected by RT-PCR, with 50% of these observed to be weak LFD positives. At lower viral loads, such as 10,000-100,000 RNA copies/ml, the LFD detected 22.2% of positives. In addition, two strong positives (3 and 1.5 million RNA copies/ml) were not detected by the LFD. Conclusion: The argument for use of LFD kits is that they detect infectious virus and hence contagious individuals. However, there is a lack of conclusive evidence supporting this claim. The Innova LFD has been subject to a Class I recall by the US Food and Drug Administration, but is still approved and widely used in the United Kingdom.

Corrigendum: Hepatitis B Virus (HBV) Infection and Re-activation During Nucleos(t)ide Reverse Transcriptase Inhibitor-Sparing Antiretroviral Therapy in a High-HBV Endemicity Setting.

[This corrects the article DOI: 10.1093/ofid/ofy251.].

Hepatitis B Virus (HBV) Infection and Re-activation During Nucleos(t)ide Reverse Transcriptase Inhibitor-Sparing Antiretroviral Therapy in a High-HBV Endemicity Setting.

BACKGROUND: We monitored the evolution of markers of hepatitis B virus (HBV) infection in virologically suppressed HIV-positive patients switching to nucleoside reverse transcriptase inhibitor (NRTI)-sparing antiretroviral therapy within a randomized trial in Cameroon. METHODS: HBV surface antigen (HBsAg), HBV DNA, and antibodies against surface (anti-HBs), core (total anti-HBc), and e-antigen (anti-HBe) were measured retrospectively in samples collected at study entry and over 48 weeks after NRTI discontinuation. RESULTS: Participants (n = 80, 75% females) had a plasma HIV-1 RNA <60 copies/mL, a median CD4 count of 466 cells/mm3, and undetectable HBsAg and HBV DNA at study entry. After NRTI discontinuation, 3/20 (15.0%) anti-HBc-negative patients showed evidence indicative or suggestive of incident HBV infection (163 cases/1000 person-years); 6/60 (10.0%) anti-HBc-positive patients showed evidence indicative or suggestive of HBV reactivation (109 cases/1000 person-years). In one case of reactivation, anti-HBs increased from 14 to >1000 IU/L; sequencing showed HBV genotype A3 and 3 escape mutations in surface (Y100C, K122R, Y161FY). Alongside new-onset detection of HBsAg or HBV DNA, 1 patient experienced acute hepatitis and 6 patients experienced mild or marginal increases in serum transaminase levels. CONCLUSIONS: Evolving treatment strategies for sub-Saharan Africa must be accompanied by the formulation and implementation of policy to guide appropriate assessment and management of HBV status.

Opportunities for life course research through the integration of data across Clinical and Translational Research Institutes.

INTRODUCTION: Early life exposures affect health and disease across the life course and potentially across multiple generations. The Clinical and Translational Research Institutes (CTSIs) offer an opportunity to utilize and link existing databases to conduct lifespan research. METHODS: A survey with Lifespan Domain Taskforce expert input was created and distributed to lead lifespan researchers at each of the 64 CTSIs. The survey requested information regarding institutional databases related to early life exposure, child-maternal health, or lifespan research. RESULTS: Of 64 CTSI, 88% provided information on a total of 130 databases. Approximately 59% (n=76/130) had an associated biorepository. Longitudinal data were available for 72% (n=93/130) of reported databases. Many of the biorepositories (n=44/76; 68%) have standard operating procedures that can be shared with other researchers. CONCLUSIONS: The majority of CTSI databases and biorepositories focusing on child-maternal health and lifespan research could be leveraged for lifespan research, increased generalizability and enhanced multi-institutional research in the United States.

Assessing the use of hospital staff influenza-like absence (ILA) for enhancing hospital preparedness and national surveillance.

BACKGROUND: Early warning and robust estimation of influenza burden are critical to inform hospital preparedness and operational, treatment, and vaccination policies. Methods to enhance influenza-like illness (ILI) surveillance are regularly reviewed. We investigated the use of hospital staff 'influenza-like absences' (hospital staff-ILA), i.e. absence attributed to colds and influenza, to improve capture of influenza dynamics and provide resilience for hospitals. METHODS: Numbers and rates of hospital staff-ILA were compared to regional surveillance data on ILI primary-care presentations (15-64 years) and to counts of laboratory confirmed cases among hospitalised patients from April 2008 to April 2013 inclusive. Analyses were used to determine comparability of the ILI and hospital-ILA and how systems compared in early warning and estimating the burden of disease. RESULTS: Among 20,021 reported hospital-ILA and 4661 community ILI cases, correlations in counts were high and consistency in illness measurements was observed. In time series analyses, both hospital-ILA and ILI showed similar timing of the seasonal component. Hospital-ILA data often commenced and peaked earlier than ILI according to a Bayesian prospective alarm algorithm. Hospital-ILA rates were more comparable to model-based estimates of 'true' influenza burden than ILI. CONCLUSIONS: Hospital-ILA appears to have the potential to be a robust, yet simple syndromic surveillance method that could be used to enhance estimates of disease burden and early warning, and assist with local hospital preparedness.

Co-morbidities in children presenting with chronic suppurative otitis media--a South African study.

BACKGROUND: Chronic suppurative otitis media (CSOM) is common among children in southern Africa. Managing associated co-morbidities may result in earlier disease resolution. METHODS: Children <13 years of age with otorrhoea lasting >4 weeks were recruited to the study. Each child underwent a full clinical examination, a blood count, an HIV test and CD4 cell count, if found to be infected. RESULTS: The study included 86 children, and the median age was 4.6 years. HIV infection was present in 45 of 83 children (54.2%), of which 23 (51.1%) were receiving antiretroviral treatment at the time of presentation. Underweight was present in 22 of 85 (25.9%) children and in 17 of the 45 (37.8%) HIV-infected children. One or more clinical signs (not aural-related) were found in 46 of 86 (53.4%) children. Cholesteatoma was found in 23 of 113 (20.4%) ears, and 9 of 86 (10.5%) children had serious associated aural or intracranial complications. CONCLUSIONS: A high percentage of children with CSOM have associated pathology that needs to be diagnosed to optimally manage CSOM.

Non-immunogenicity of overlapping gag peptides pulsed on autologous cells after vaccination of HIV infected individuals.

BACKGROUND: HIV Gag-specific CD4+ and CD8+ T-cell responses are important for HIV immune control. Pulsing overlapping Gag peptides on autologous lymphocytes (OPAL) has proven immunogenic and effective in reducing viral loads in multiple pigtail macaque studies, warranting clinical evaluation. METHODOLOGY: We performed a phase I, single centre, placebo-controlled, double-blinded and dose-escalating study to evaluate the safety and preliminary immunogenicity of a novel therapeutic vaccine approach 'OPAL-HIV-Gag(c)'. This vaccine is comprised of 120 15mer peptides, overlapping by 11 amino acids, spanning the HIV Gag C clade sequence proteome, pulsed on white blood cells enriched from whole blood using a closed system, followed by intravenous reinfusion. Patients with undetectable HIV viral loads (<50 copies/ml plasma) on HAART received four administrations at week 0, 4, 8 and 12, and were followed up for 12 weeks post-treatment. Twenty-three people were enrolled in four groups: 12 mg (n = 6), 24 mg (n = 7), 48 mg (n = 2) or matching placebo (n = 8) with 18 immunologically evaluable. T-cell immunogenicity was assessed by IFNγ ELIspot and intracellular cytokine staining (ICS). RESULTS: The OPAL-HIV-Gag(c) peptides were antigenic in vitro in 17/17 subjects. After vaccination with OPAL-HIV-Gag(c), 1/6 subjects at 12 mg and 1/6 subjects at 24 mg dose groups had a 2- and 3-fold increase in ELIspot magnitudes from baseline, respectively, of Gag-specific CD8+ T-cells at week 14, compared to 0/6 subjects in the placebo group. No Gag-specific CD4+ T-cell responses or overall change in Rev, Nef, Tat and CMV specific responses were detected. Marked, transient and self-limiting lymphopenia was observed immediately post-vaccination (4 hours) in OPAL-HIV-Gag(c) but not in placebo recipients, with median fall from 1.72 to 0.67 million lymphocytes/mL for active groups (P<0.001), compared to post-placebo from 1.70 to 1.56 lymphocytes/ml (P = 0.16). CONCLUSION/SIGNIFICANCE: Despite strong immunogenicity observed in several Macaca nemestrina studies using this approach, OPAL-HIV-Gag(c) was not significantly immunogenic in humans and improved methods of generating high-frequency Gag-specific T-cell responses are required. NAME OF REGISTRY: ClinicalTrials.gov, Registry number: NCT01123915, URL trial registry database: http://www.clinicaltrials.gov/ct2/results?term=OPAL-HIV-1001&Search=Search.

A randomised, placebo-controlled, first-in-human study of a novel clade C therapeutic peptide vaccine administered ex vivo to autologous white blood cells in HIV infected individuals.

BACKGROUND: Preclinical studies of overlapping 15mer peptides, spanning SIV, SHIV or HIV, pulsed on autologous PBMC ex vivo have demonstrated high level, virus-specific T cell responses and viral suppression in non-human primates (NHP). Opal-HIV-Gag(c) consists of 120 synthetic 15mer peptides spanning Clade C, consensus Gag, manufactured to current good manufacturing practice; having been evaluated in a good laboratory practice toxicology study in Macaca mulatta. We evaluated the safety and preliminary immunogenicity of such peptides administered intravenously after short-duration ex vivo incubation, to HIV-positive adults on suppressive antiretroviral therapy. METHODS AND FINDINGS: A first-in-human, placebo-controlled, double-blind, dose escalation study was conducted. Twenty-three patients with virus suppressed by antiretroviral therapy were enrolled in four groups 12 mg (n = 6), 24 mg (n = 6), 48 mg (n = 2) or matching placebo (n = 8). Treatment was administered intravenously after bedside enrichment of 120 mL whole blood for white cells using a closed system (Sepax S-100 device), with ex vivo peptide admixture (or diluent alone) and 37°C incubation for one hour prior to reinfusion. Patients received 4 administrations at monthly intervals followed by a 12-week observation post-treatment. Opal-HIV-Gag(c) was reasonably tolerated at doses of 12 and 24 mg. There was an increased incidence of temporally associated pyrexia, chills, and transient/self-limiting lymphopenia in Opal-HIV-Gag(c) recipients compared to placebo. The study was terminated early, after two patients were recruited to the 48 mg cohort; a serious adverse event of hypotension, tachycardia secondary to diarrhoea occurred following a single product administration. An infectious cause for the event could not be identified, leaving the possibility of immunologically mediated product reaction. CONCLUSIONS: A serious, potentially life-threatening event of hypotension led to early, precautionary termination of the study. In the absence of a clearly defined mechanism or ability to predict such occurrence, further development of Opal-HIV-Gag(c) will not be undertaken in the current form. REGISTRATION: ClinicalTrials.gov NCT01123915; EudraCT: 2008-005142-23.

Chronic Hepatitis E as a cause for cryptogenic cirrhosis in HIV.

Chronic Hepatitis E infection (HEV) is reported in immunocompromised patients. A 45-year-old HIV-infected man had no cause found for a persistent transaminitis which predated commencement of antiretroviral therapy. Hepatic elastography and liver biopsy revealed cirrhosis. In 2010, he tested positive for HEV IgM/IgG antibodies. Plasma HEV RNA was detected. Archived samples revealed HEV viraemia since 2000. A 24-week course of pegylated interferon was commenced and HEV RNA became undetectable at week 4 until week 27 post treatment cessation. Chronic HEV infection should be considered in HIV patients as a cause for unexplained transaminitis and cryptogenic liver cirrhosis.

Exploring staff attitudes to routine HIV testing in non-traditional settings: a qualitative study in four healthcare facilities.

OBJECTIVES: To explore staff attitudes towards and experiences of the implementation of routine HIV testing in four healthcare settings in areas of high diagnosed HIV prevalence. METHODS: As part of the HINTS (HIV Testing in Non-traditional Settings) Study, routine offer of an HIV test to all 16-65-year-old patients was conducted for 3 months in an emergency department, an acute admissions unit, a dermatology outpatients department and a primary care practice. The authors conducted focus groups with staff at these sites before and after the implementation of testing. Transcriptions of focus groups were subject to thematic analysis. RESULTS: Four major themes were identified: the stigma of HIV and exceptionalisation of HIV testing as a condition; the use of routine testing compared with a targeted strategy as a means of improving the acceptability of testing; the need for an additional skill set to conduct HIV testing; and the existence within these particular settings of operational barriers to the implementation of HIV testing. Specifically, the time taken to conduct testing and management of results were seen by staff as barriers. There was a clear change in staff perception before and after implementation of testing as staff became aware of the high level of patient acceptability. CONCLUSIONS: The routine offer of HIV testing in general medical services is feasible, but implementation requires training and support for staff, which may be best provided by the local sexual health service.

HIV testing in non-traditional settings--the HINTS study: a multi-centre observational study of feasibility and acceptability.

BACKGROUND: UK guidelines recommend routine HIV testing in healthcare settings if the local diagnosed HIV prevalence >2/1000 persons. This prospective study assessed the feasibility and acceptability, to patients and staff, of routinely offering HIV tests in four settings: Emergency Department, Acute Care Unit, Dermatology Outpatients and Primary Care. Modelling suggested the estimated prevalence of undiagnosed HIV infection in attendees would exceed 1/1000 persons. The prevalence identified prospectively was not a primary outcome. METHODS: Permanent staff completed questionnaires assessing attitudes towards routine HIV testing in their workplace before testing began. Subsequently, over a three-month period, patients aged 16-65 were offered an HIV test by study staff. Demographics, uptake, results, and departmental activity were collected. Subsets of patients completed questionnaires. Analyses were conducted to identify factors associated with test uptake. FINDINGS: Questionnaires were received from 144 staff. 96% supported the expansion of HIV testing, but only 54% stated that they would feel comfortable delivering testing themselves, with 72% identifying a need for training. Of 6194 patients offered a test, 4105 (66·8%) accepted (61·8-75·4% across sites). Eight individuals were diagnosed with HIV (0-10/1000 across sites) and all transferred to care. Younger people, and males, were more likely to accept an HIV test. No significant associations were found between uptake and ethnicity, or clinical site. Questionnaires were returned from 1003 patients. The offer of an HIV test was acceptable to 92%. Of respondents, individuals who had never tested for HIV before were more likely to accept a test, but no association was found between test uptake and sexual orientation. CONCLUSIONS: HIV testing in these settings is acceptable, and operationally feasible. The strategy successfully identified, and transferred to care, HIV-positive individuals. However, if HIV testing is to be included as a routine part of patients' care, additional staff training and infrastructural resources will be required.

Development and validation of an efficient in-house real-time reverse transcription polymerase chain reaction assay for the quantitative detection of serum hepatitis delta virus RNA in a diverse South London population.

Hepatitis delta virus (HDV) causes both acute and chronic hepatitis, always in the presence of hepatitis B. Analysis of global HDV isolates has shown that at least eight genotypes exist. HDV RNA quantitation and genotyping are important tools in the diagnosis and management of infected individuals. There is, as yet, no commercially available quantitative HDV RNA assay. Several laboratories have developed in-house assays, but equivalent detection and quantitation across all HDV genotypes has not been demonstrated. In this study, the development of an in-house real-time reverse transcription polymerase chain reaction (RT PCR) assay is described to quantify HDV RNA in serum or plasma. Its efficiency was validated by testing 99 samples from patients with known chronic HDV infection, along with 22 samples from individuals without HDV. The assay has a dynamic range of 6.4×10(2) to 6.4×10(8)copies/mL. Amplicons of the quantitative PCR can be directly used for sequence analysis and genotyping. HDV-1, HDV-5 and HDV-6 were identified, reflecting the areas of origin of our cohort of patients. The ability to genotype and to accurately quantify HDV RNA levels in the more recently discovered African genotypes will be important for investigating the natural history of HDV in this group, compared to those with genotype 1 disease.

Humoral and cellular immunity to primary H1N1 infection in patients with hematologic malignancies following stem cell transplantation.

Limited data are available on immunologic responses to primary H1N1 infection in patients with hematologic malignancies. We present a prospective, case-surveillance study of such patients with real-time polymerase chain reaction (RT-PCR) confirmed H1N1-influenza who presented to our institution between September 2009 and January 2010. Ninety-two patients presented with influenza-like symptoms, and 13 had H1N1 infection confirmed by RT-PCR, including 4 allogeneic stem cell transplant recipients (1 with acute myelogenous leukemia, 1 with chronic lymphoblastic leukemia [CLL], 1 with non-Hodgkin lymphoma, and 1 with chronic myelogenous leukemia), 5 patients with multiple myeloma following autologous stem cell transplantation, 1 patient with multiple myeloma perimobilization, 2 patients with NHL post chemotherapy, and 1 patient with CLL. All 13 patients required hospitalization. Six (43%) were admitted to the intensive care unit (ICU), of whom 4 (67%) died. We evaluated B cell and T cell responses to H1N1 infection prospectively in these patients compared with those in 4 otherwise healthy controls. Within 12 weeks of diagnosis, only 6 of 11 patients developed seropositive antibody titers as measured by hemagglutination-inhibition or microneutralization assays, compared with 4 of 4 controls. H1N1-specific T cells were detected in only 2 of 8 evaluable patients compared with 4 of 4 controls. H1N1-specific T cells were functional, capable of producing interferon γ, tumor necrosis factor α, and CD107a mobilization. Furthermore, CD154 was up-regulated on CD4(+) T cells in 3 of 4 controls and 2 of 2 patients who had both B cell and T cell responses to H1N1. Post-H1N1 infection, 5 of 8 patients developed seasonal influenza-specific T cells, suggesting cross-reactivity induced by H1N1 infection. These data offer novel insights into humoral and cell-mediated immunologic responses to primary H1N1 infection.

Clearance of hepatitis C virus RNA from serum in HIV/hepatitis C virus coinfection indicates eradication from peripheral blood mononuclear cells.

OBJECTIVES: The objectives of this study are to determine the frequency of hepatitis C virus (HCV) RNA persistence in peripheral blood mononuclear cells (PBMCs) of HIV-positive patients with clearance of the virus from serum and to identify the presence of any ongoing replication. DESIGN: This is a prospective cross-sectional study. METHODS: HIV antibody-positive individuals with previous exposure to HCV, but not current infection with HCV, were recruited. Blood was taken to allow identification of HCV RNA in both serum and PBMCs. Intracellular HCV was extracted using the QIAamp RNA Blood MiniKit. Reverse transcriptase-PCR was performed using a modification of the COBAS TaqMan HCV Test for use with the high pure system. RESULTS: Twenty-six HIV-positive individuals were recruited to the study. All had previously been infected with HCV. Six individuals had spontaneously cleared HCV, 10 had achieved sustained virological response following 24 weeks of pegylated interferon and ribavirin for acute HCV, and 10 had achieved sustained virological response following standard pegylated interferon and ribavirin therapy for chronic HCV. None demonstrated HCV RNA persistence in either serum or PBMCs. CONCLUSION: Our findings lend support to the view that clearance of HCV RNA from serum in HIV/HCV coinfection indicates eradication from PBMCs. Thus, absence of serum HCV RNA 6 months after the end of therapy can be used as a marker of treatment success for interferon-based therapies. However, the advent of small molecule HCV inhibitors may require us to rethink our definitions of response and cure.

Unselected hepatitis C screening of men who have sex with men attending sexual health clinics.

Sexual transmission of hepatitis C (HCV) between HIV positive men who have sex with men (MSM) is increasingly being reported. There is limited and conflicting data as to whether HIV negative MSM are at increased risk of infection. Local directorate guidelines recommended HCV testing only in MSM having a sexual transmitted infection (STI) screen who disclosed risk factors. In 2007 we introduced unselected screening into routine practice within our sexual health clinics. This report reviews the results of this change in our practice. Over 6 months, 3365 MSM attended for STI screening. Of 2309 MSM who agreed to be screened for HCV (69%) the prevalence of HCV was 0.65% (95% CI 0.36-1.1). This is similar to the prevalence of HCV in the general population within England. We conclude that unselected screening of MSM for HCV within our sexual health services is not currently justified.