Changes In Viral Load Research Articles

Will Complement Inhibition Be the New Target in Treating COVID-19-Related Systemic Thrombosis?

Will Complement Inhibition Be the New Target in Treating COVID-19-Related Systemic Thrombosis?

Research of simvastatin-induced autophagy in inhibiting recombinant human metapneumovirus replication

Objective To study whether simvastatin could inhibit viral replication during human metapneumovirus (hMPV) infection. Methods Human bronchial epithelial cells (16HBE) were infected with hMPV and then treated with or without simvastatin. Real-time quantitative PCR (qPCR) and Western blot were used to detect virus titers and the activation of autophagy and related pathways. BALB/c mice were infected with hMPV and then treated with simvastatin through intragastric administration. Pathological changes in lung tissues were observed. Changes in viral loads and the activation of autophagy and related pathways in proteins and RNA extracted from lung tissues were detected. Results The in vitro experiment showed that the hMPV+ simvastatin group had decreased virus titer and enhanced autophagy than the hMPV group. The AKT/mTOR pathway in the hMPV+ simvastatin group was inhibited, which was verified by a further experiment using rapamycin, a specific inhibitor of AKT/mTOR pathway. The in vivo experiment showed that the virus titer in the hMPV+ simvastatin group was lower than that in the hMPV group, but there was no significant difference in the activation of autophagy. The AKT/mTOR pathway was down-regulated in the hMPV+ simvastatin group. HE staining revealed that obvious pathological changes were observed in the hMPV group, but the condition was improved after simvastatin intervention. Conclusions Simvastatin can inhibit the replication of hMPV, which is associated with the activation of autophagy induced by AKT/mTOR pathway. Key words: Human metapneumovirus; Simvastatin; Autophagy; AKT/mTOR

Safety and efficacy of immune checkpoint inhibitors in patients with non-small cell lung cancer and hepatitis B or hepatitis C infection

ObjectivesThe safety and efficacy of immunotherapy among patients with history of hepatitis B (HBV) or hepatitis C virus (HCV) infection and non-small cell lung cancer (NSCLC) remains unclear as this population has traditionally been excluded from clinical trials with immune checkpoint inhibitors (ICIs). Materials and methodsWe retrospectively evaluated treatment toxicities and clinical outcomes in nineteen patients with NSCLC and history of past or chronic HBV (16 cases, two of these had HCV co-infection) or chronic HCV infection (five cases), who received a programmed death-1 (PD-1) pathway inhibitor. ResultsThe overall response rate to immunotherapy was 35 %, and the median progression-free survival was 4.5 months. After ICI initiation, increases in liver function tests (LFTs) from baseline were infrequent and mild, and no patients experienced grade 3 or 4 hepatic immune-related adverse events or required ICI discontinuation or corticosteroid administration for management of hepatic toxicity. There were no significant changes in viral load or cases of HBV reactivation or HCV flare while on ICI therapy. ConclusionIn this case series, treatment with immunotherapy in patients with NSCLC and past or chronic viral hepatitis appears to be safe, and responses to ICIs can be durable in this population. Additional studies are needed in larger cohorts of patients to determine the safety of immunotherapy in patients with chronic viral infections.

Perioperative Antiretroviral Regimen for HIV/AIDS Patients Who Underwent Abdominal Surgery.

A short interruption of antiretroviral therapy (ART) and reduced oral bioavailability of antiretroviral medications could occur in perioperative human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) patients who undergo abdominal surgery. Therefore, we focused on the changes in HIV viral load and CD4+ T lymphocyte count in HIV/AIDS patients after surgery and explored whether the perioperative use of intravenous antiretroviral drugs is beneficial in lowering the viral load and increasing the safety of the surgery. We prospectively collected data from HIV/AIDS patients who underwent abdominal surgery at our institution from January 2019 and April 2019. According to the use of different antiretroviral medications during the perioperative period, the HIV/AIDS patients were divided into four groups: Group I: Patients continued their original antiretroviral medications; Group II: Patients received their original antiretroviral medications plus intravenous administrationof the fusion inhibitoralbuvirtide (ABT); Group III: Patients received ABT alone; and Group IV: Patients did not receive ART. The primary outcomes considered were the changes in HIV load and CD4+ T lymphocyte count and the postoperative complications in the four groups. A total of 64 HIV/AIDS patients were enrolled, and their data were analyzed descriptively. There were no differences between group I and group II in terms of the changes in viral load. The viral load continued to decrease in group III within 30days after surgery, especially from D7 to D30 (t = 2.179, p = 0.043). However, the viral load showed an upward trend after surgery in group IV. There were statistically significant differences between the two groups in the changes in viral load after surgery (p = 0.022). However, there were no statistically significant differences between group III and group IV in the postoperative changes in the CD4+ T lymphocyte count. Seven out of 64 patients had postoperative infective complications. The incidence of complications from high to low was as follows: group IV > group I > group III > group II (p < 0.05). A short perioperative interruption of ART may have a small impact on viral load in HIV/AIDS patients on virologic suppression after abdominal surgery. For patients with a detectable viral load, an intravenous injection of ABT in the perioperative period can reduce the viral load quickly, lower the occurrence of postoperative complications, and increase operation safety for both the HIV/AIDS patient and the surgeons.

HIV Treatment Initiation and Retention Among Individuals Initiated on Injectable Opioid Agonist Therapy for Severe Opioid Use Disorder: A Case Series.

Injectable opioid agonist therapy (iOAT) has previously been demonstrated to be an effective treatment option for individuals with a severe opioid use disorder (OUD) who have been unsuccessful on first line therapy (eg, buprenorphine/naloxone or methadone). Many individuals with severe OUD may also have HIV infection. Despite this, no literature currently exists examining the relationship between antiretroviral therapy (ART) initiation and adherence following iOAT initiation in the outpatient setting. Retrospective case series (n = 3) of HIV-infected individuals with a severe OUD who were refractory to oral opioid agonist treatment and were started on iOAT in a community setting in Vancouver, Canada. Outcomes of interest included: (1) iOAT induction and maintenance dosing schedules; (2) ART adherence demonstrated by change in HIV viral load. All 3 patients initiated and successfully reached iOAT maintenance doses with significant reduction in illicit opioid use. Stable iOAT was associated with increased ART initiation and adherence, and decreased HIV viral loads. Conversely, poor retention or discontinuation of iOAT was associated with reduced adherence to ART and in 1 patient, increased HIV viral loads. The individual cases presented suggest that among individuals with severe OUD and HIV infection, iOAT may improve HIV treatment uptake and retention in care.

NGF (\u2212198C\u2009>\u2009T, Ala35Val) and p75NTR (Ser205Leu) gene mutations are associated with liver function in different histopathological profiles of the patients with chronic viral hepatitis in the Brazilian Amazon

BackgroundsNeural growth factor (NGF) is a neurotrophin that can interact with the p75NTR receptor and initiate a cascade of reactions that determines cell survival or death, and both are associated with the physiology of liver tissue. Single nucleotide polymorphisms (SNPs) in the NGF and p75NTR genes have been investigated in different pathologies; however, there are no studies that have analyzed their biological roles in the hepatic microenvironment. In the present study, we evaluated the impact of SNPs in these genes on the maintenance of liver function at different stages of inflammation and fibrosis in patients with chronic viral liver disease in the Brazilian Amazon.MethodsThe SNPs -198C > T, Arg80Gln, Val72Met, Ala35Val, Ala18Ala and Ser205Leu were genotyped by real-time PCR in samples from patients with chronic viral hepatitis stratified by stage of inflammation and liver fibrosis. Histopathological, viral load (VL), liver enzyme and comorbidities data were obtained from updated medical records. Other aspects were highlighted by applied epidemiological questionnaires.ResultsThe -198C/T and Ala35Val polymorphisms in NGF were associated with changes in histopathological profiles, VL and liver enzymes. Ser205Leu polymorphism in p75NTR was associated only with changes in VL and liver enzymes. Polymorphic frequencies were variable among different ethnic populations, mainly for biologically relevant polymorphisms. A multifactorial network of interactions has been established based on genetic, virological, behavioral and biochemical aspects.ConclusionMutations in the NGF (−198C > T, Ala35Val) and p75NTR (Ser205Leu) genes, within the list of multifactorial aspects, are associated with liver function in different histopathological profiles of patients with chronic viral liver disease in the Brazilian Amazon.

A Quality Improvement Project to Increase Patient Portal Enrollment and Utilization in Women Living With HIV at Risk for Disengagement in Care.

Women living with HIV are less likely to be retained and engaged in consistent care than their male counterparts. The purpose of this quality improvement project was to increase the enrollment and utilization rate of a patient portal, an mHealth technology, by women living with HIV at risk of disengagement in care to improve their overall engagement and retention in care. At-risk women were identified, educated on, and enrolled in a patient portal system during routine clinic appointments. Engagement was measured using portal utilization rates and patient-initiated communication and analyzed using descriptive statistics. Paired 2-tailed Student t-tests were used to evaluate changes in adherence rates, viral loads, and CD4 T-cell counts from 90-day pre-enrollment to 90-day post-enrollment. Overall results indicate improved utilization and engagement through the use of a patient portal system are feasible in this population and promote engagement and retention in care.

A Phase 2b, Randomized, Double-blind, Placebo-Controlled Multicenter Study Evaluating Antiviral Effects, Pharmacokinetics, Safety, and Tolerability of Presatovir in Hematopoietic Cell Transplant Recipients with Respiratory Syncytial Virus Infection of the Lower Respiratory Tract.

BackgroundPresatovir significantly reduced nasal viral load, signs, and symptoms of respiratory syncytial virus (RSV) infection in a human challenge study. We evaluated presatovir in hematopoietic-cell transplant (HCT) recipients with RSV lower respiratory tract infection (LRTI).MethodsPatients with confirmed RSV in upper and lower respiratory tract and new chest X-ray abnormalities were randomized (1:1), stratified by supplemental oxygen and ribavirin use, to receive oral presatovir 200 mg or placebo every 4 days for 5 doses. The primary endpoint was time-weighted average change in nasal RSV viral load through day 9. Secondary endpoints included supplemental oxygen-free days, incident respiratory failure requiring mechanical ventilation, and all-cause mortality.ResultsFrom January 31, 2015, to March 20, 2017, 60 patients from 17 centers were randomized (31 presatovir, 29 placebo); 59 received study treatment (50 allogeneic, 9 autologous HCT). In the efficacy population (29 presatovir, 28 placebo), presatovir treatment did not significantly reduce time-weighted average change in viral load (−1.12 vs −1.09 log10 copies/mL; treatment difference −0.02 log10 copies/mL, 95% confidence interval: −.62, .57; P = .94), median supplemental oxygen-free days (26 vs 28 days, P = .84), incident respiratory failure (10.3 vs 10.7%, P = .98), or all-cause mortality (0 vs 7.1%, P = .19) versus placebo. Adverse events were similar between arms (presatovir 80%, placebo 79%). Resistance-associated substitutions in RSV fusion protein emerged in 6/29 presatovir-treated patients.ConclusionsPresatovir treatment was well tolerated in HCT patients with RSV LRTI but did not improve virologic or clinical outcomes versus placebo.Clinical Trials Registration www.clinicaltrials.gov, NCT02254421; EudraCT, #2014-002475-29

Safety and efficacy of immune checkpoint inhibitors (ICIs) in cancer patients with HIV, hepatitis B, or hepatitis C viral infection

sBackgroundPatients with chronic viral infections including human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV) are at increased risk of developing malignancies. The safety and efficacy of ICI therapy in patients with both cancer and chronic viral infections is not well established as most clinical trials of ICIs excluded these patient populations.MethodsWe performed a retrospective analysis of patients with advanced-stage cancers and HIV, HBV, or HCV infection treated with ICI therapy at 5 MedStar Health hospitals from January 2011 to April 2018.ResultsWe identified 50 patients including 16 HIV, 29 HBV/HCV, and 5 with concurrent HIV and either HBV or HCV. In the HIV cohort (n = 21), any grade immune-related adverse events (irAEs) were 24% with grade ≥ 3 irAEs 14%. Among 5 patients with matched pre/post-treatment results, no significant changes in HIV viral load and CD4+ T-cell counts were observed. RECIST confirmed (n = 18) overall response rate (ORR) was 28% with 2 complete responses (CR) and 3 partial responses (PR). Responders included 2 patients with low baseline CD4+ T-cell counts (40 and 77 cells/ul, respectively). In the HBV/HCV cohort (n = 34), any grade irAEs were 44% with grade ≥ 3 irAEs 29%. RECIST confirmed ORR was 21% (6 PR). Among the 6 patients with known pre/post-treatment viral titers (2 HCV and 4 HBV), there was no evidence of viral reactivation.ConclusionsOur retrospective series is one of the largest case series to report clinical outcomes among HIV, HBV and HCV patients treated with ICI therapy. Toxicity and efficacy rates were similar to those observed in patients without chronic viral infections. Viral reactivation was not observed. Tumor responses occurred in HIV patients with low CD4 T-cell counts. While prospective studies are needed to validate above findings, these data support not excluding such patients from ICI–based clinical trials or treatment.

Stability of hepatitis B viral load during pregnancy and implications for antepartum prophylaxis: A prospective cohort study.

We examined changes in hepatitis B virus (HBV) viral loads (VLs) in pregnancy, their association with hepatitis B e antigen (HBeAg), and the associated infant outcomes. We prospectively followed 132 mothers positive for hepatitis B surface antigen (HBsAg) and their 135 infants from 2011 to 2015 in Vancouver, British Columbia. Outcome measures included association between maternal HBeAg and high (>200,000 IU/mL) or low (≤200,000 IU/mL) HBV VL, changes in HBV VL through pregnancy, infant HBsAg status, and infant completion of the HBV vaccination series. f the 91 participants with an available HBV VL, 13 (14.3%) had an HBV VL of more than 200,000 IU/mL. Of 59 participants with paired HBeAg and HBV VL in pregnancy, 6 had an HBV VL of more than 200,000 IU/mL; of interest, 2 of the 6 (33.3%) were HBeAg-negative. Thirty-eight participants had HBV VL results at both mid-trimester and delivery. For these 38 participants, Wilcoxon signed-ranks test for paired data found that an HBV VL remained stable (p = .58). We observed no perinatal transmissions. However, 20.7% of infants did not have a documented complete HBV vaccination series, 20.0% did not have post-vaccination HBsAg testing completed, and 18% did not have anti-HBs titres measured by age 12 months. Our study demonstrates that HBeAg and HBV VL are not reliably predictive of each other. This supports the improved predictive value of VL measurement in pregnancy to risk stratify pregnant patients to offer antiviral treatment when indicated and further minimize the risk of perinatal transmission.

843. The PALM Consortium: A Multicenter, Multioutbreak Randomized Controlled Trial of Ebola Virus Disease Therapeutics

BackgroundRecent outbreaks of Ebola virus disease in the Democratic Republic of the Congo (DRC) reinforce the desperate need to establish definitively the comparative safety and efficacy of different medical countermeasures (MCM).MethodsThrough a multipartner governance framework under WHO coordination, the Institut National de Recherche Biomédicale and NIAID collaborated with clinical partners (the MOH, ALIMA, MSF) to launch a randomized controlled trial in 2018 in the North Kivu/Ituri provinces of DRC. PCR+ participants receiving enhanced supportive care are being randomized 1:1:1:1 to receive either ZMapp™ (control arm), remdesivir, mAb114, or REG-EB3 according to standard treatment regimens. Stratification is by site, country, and baseline nucleoprotein (NP) PCR cycle threshold (CT) ≤ 22 or > 22. The primary objective is a comparison of 28-day mortality relative to the control arm. The planned accrual is for 125 patients per arm. Secondary objectives include an evaluation of the comparative safety and tolerability of the 4 investigational MCMs, relative changes in viral load over time, comparisons of treatment efficacy according to baseline risk categories, 58-day mortality, RNA clearance from semen, and an assessment of the validity of drug-class comparisons, including efficacy. The study is monitored by an independent data and safety monitoring committee (DSMB).ResultsEnrollment commenced in the Ebola Treatment Unit in Beni in November, 2018, with sites in Butembo and Katwa added in early 2019. Time from study concept initiation to study start was only 3.5 months. Ongoing hurdles encountered to date include maintenance of cold chain requirements for the MCMs and marked volatility in the security situation surrounding sites affecting staff and patient safety. Despite these challenges, data quality and completed follow-up have been remarkably high and by mid-April, 2019, accrual to date (see table) had already surpassed the predefined threshold triggering an interim DSMB review.ConclusionScientifically rigorous and ethically sound clinical research can take place during disease outbreaks even within a conflict zone. Results about the relative efficacy of the evaluated investigational MCMs are pending the completion of the trial. Disclosures All Authors: No reported Disclosures.

661. Ibalizumab Efficacy and Safety Through 48 Weeks of Treatment: Results of an Expanded Access Protocol (TMB-311)

BackgroundIbalizumab (IBA), a humanized monoclonal antibody, is the first CD4-directed post-attachment HIV-1 inhibitor. It was approved by the FDA in March 2018 based on results from the pivotal Phase 3 TMB-301 clinical study.The TMB-311 expanded access protocol Cohort 2 enrolled treatment-experienced patients with multidrug-resistant (MDR) HIV-1 infection to further evaluate the efficacy, safety and tolerability of IBA in combination with an optimized background regimen (OBR). Here, we report the results through 48 weeks of treatment in these patients.MethodsMajor eligibility criteria included HIV-1 viral load (VL) >1000 copies/mL, resistance to ≥1 antiretroviral (ARV) medication from three different ARV classes and full viral sensitivity to ≥1 ARV agent. Treatment started with IBA 2000 mg intravenously (IV) on Day 0 and then 800 mg IV (maintenance) every 2 weeks thereafter. OBR with ≥1 fully active agent also started at Day 0.ResultsCohort 2 enrolled 38 patients with a median age of 53 years, mostly male (87%) and white (53%). At Baseline, median VL was 4.7 log10 copies/mL, CD4 cell count was 26 cells/mm3 and overall susceptibility score of 1. A ≥0.5 log10 decrease in VL from Baseline was achieved in 28 of 37 patients (76%) at Day 7. Of 24 patients who completed the Week 24 visit, 11 (46%) had HIV-1 RNA levels <50 copies/mL. Of 17 patients with a VL assessment at Week 48, 8 (47%) achieved <50 copies/mL. Seven patients did not have a Week 48 endpoint because they withdrew from the study to receive commercial IBA. At both time points, the median change in VL from Baseline was -2.6 log10 copies/mL. The most frequently reported treatment-emergent adverse events (TEAEs) were diarrhea (24%), headache (21%), and nausea, cough, rash, and fatigue (16% each). No injection site reactions related to IBA were reported. Most events were mild; 9 patients reported Grade ≥3 TEAEs. Two events were fatal (sepsis and cardiac arrest); neither related to IBA. One event of immune reconstitution inflammatory syndrome was reported and considered possibly related to IBA.ConclusionResults from Cohort 2 patients of TMB-311 (IBA + OBR) demonstrate durable viral suppression in this difficult-to-treat patient population and with a safety profile consistent with pivotal Phase 3 study of IBA.Disclosures All authors: No reported disclosures.

Benefits and Limits of Antiretroviral Drug Monitoring in Routine Practice

HIV infection is a chronic disease for which therapeutic adherence and tolerance require particular attention. This study aimed to assess whether and when therapeutic drug monitoring (TDM) could be associated with a benefit in routine practice. All HIV-infected patients who underwent at least one TDM at the University Hospital of Dijon (France) between 1st January 2009 and 31st December 2012 were retrospectively included. Compliance with the recommendations, the results (antiretroviral concentrations), any subsequent therapeutic modifications, and the virological results at 4-8 months were analysed each time TDM was performed. TDM was defined as "practically relevant" when low or high antiretroviral concentrations led to a change in therapy. Of the 571 patients who followed-up, 43.4% underwent TDM. TDM complying with recommendations (120 patients) was associated with a higher proportion of antiretroviral concentrations outside the therapeutic range (p=0.03). Antiretroviral treatment was modified after TDM in 22.6% of patients. Protease inhibitors, non-nucleoside reverse transcriptase inhibitors and raltegravir were more significantly modified when the measured concentration was outside the therapeutic range (p=0.008, p=0.05 and p=0.02, respectively). Overall, 11.7% of TDM was considered "practically relevant", though there was no significant correlation between subsequent changes in antiretroviral treatment and undetectable final HIV viral load. TDM may be a useful tool in the management of HIV infection in specific situations, but the overall benefit seems moderate in routine practice. TDM cannot be systematic and/or a decision tool per se, but should be included in a comprehensive approach in certain clinical situations.

964 Patient Flow Across Physician Specialties Over the Course of the Hepatitis C Care Cascade: A Real World Analysis From the United States

INTRODUCTION: Hepatitis C virus (HCV) infection is a major cause of hepatic and extrahepatic morbidity and mortality. In spite of recommendations for HCV screening, diagnosis, linkage to care and treatment, significant gaps remain in the cascade of care for HCV. As the role of physician specialties for closing these gaps is poorly understood, this study assesses the flow of HCV patients across physician specialties in the US, over the course of the care cascade. METHODS: This retrospective real-world study used two large de-identified national laboratory datasets (2013–2016). Screened patients had a HCV antibody (AB) test and/or HCV RNA viral load test. Diagnosed patients had a positive HCV RNA viral load test, and among this group, fibrosis assessment, genotype test and treatment were evaluated. Treatment was inferred with an algorithm based on changes in viral load. The number/proportion of patients at each step in the care cascade was calculated by physician specialty. Patient flow by physician specialty over the course of care cascade was assessed using Sankey Diagrams. RESULTS: Approximately 17 million patients received HCV screening, and 913,529 were diagnosed. Over the course of the care cascade, there was an increase in the proportion of patients switching to HCV specialists (gastroenterologist, hepatologist, and infectious disease specialist). Generalists (primary care, family practice, internal medicine) ordered 37% of the AB tests, and 15% initiated treatment. HCV specialists ordered 3% of screening tests and 37% initiated treatment. Most of the fibrosis assessment (30%) and genotype tests (29%) were ordered by HCV specialists. Obstetricians/gynecologists ordered 11% of screening tests but only 0.3% initiated treatment. Among 974,277 patients who received a positive AB test, 46% did not receive a confirmatory RNA test. Among diagnosed patients, 57% did not receive fibrosis assessment, 47% did not receive genotype test and 90% did not receive treatment. CONCLUSION: Generalists account for more than one third of all HCV screening tests, however, HCV specialists play a more prominent role in patient assessment (fibrosis status, genotype testing) and treatment. Significant gaps remain in all stages of the cascade of care for HCV, and improved efforts are needed for every physician specialty to address them. Timely screening, monitoring and linkage to care by generalists coupled with early treatment by specialists could effectively reduce the hepatic and extrahepatic burden of HCV.

Switching from a regimen containing abacavir/lamivudine or emtricitabine/tenofovir disoproxil fumarate to emtricitabine/tenofovir alafenamide fumarate does not affect central nervous system HIV-1 infection

Background: Despite suppressive antiretroviral therapy (ART), many HIV-infected individuals have low-level persistent immune activation in the central nervous system (CNS). There have been concerns regarding the CNS efficacy of tenofovir alafenamide fumarate (TAF) because of its low cerebrospinal fluid (CSF) concentrations and because it is a substrate of the active efflux transporter P-glycoprotein. Our aim was to investigate whether switching from emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) or abacavir (ABC)/lamivudine (3TC) to FTC/TAF would lead to changes in residual intrathecal immune activation, viral load, or neurocognitive function.Methods: Twenty HIV-1-infected neuro-asymptomatic adults (11 on ABC/3TC and 9 on FTC/TDF) were included in this prospective study. At baseline, all participants changed their nucleoside analogues to FTC/TAF without any other changes in their ART regimen. We performed lumbar punctures, venipunctures, and neurocognitive testing at baseline and after three and 12 months.Results: During follow-up, there were no significant changes in CSF or plasma HIV RNA, CSF neopterin, CSF β2-microglobulin, IgG index, albumin ratio, CSF NFL, or neurocognitive function in assessed by Cogstate in any of the groups.Conclusion: This small pilot study indicates that switching to FTC/TAF from ABC/3TC or FTC/TDF has neither a positive, nor a negative effect on the HIV infection in the CNS.

Evaluating the reactivation of herpesviruses and inflammation as cardiovascular and cerebrovascular risk factors in antiretroviral therapy initiators in an African HIV-infected population (RHICCA): a protocol for a longitudinal cohort study

IntroductionIn Sub-Saharan Africa, the rising rates of cerebrovascular and cardiovascular diseases (CBD/CVD) are intersecting with an ageing HIV-infected population. The widespread use of antiretroviral therapy (ART) may confer an additive...

Changes in DNA Level of Oncogenic Human Papillomaviruses Other Than Types 16 and 18 in Relation to Risk of Cervical Intraepithelial Neoplasia Grades 2 and 3.

Epidemiologic data addressing clinical relevance of viral load fluctuation of oncogenic types other than human papillomavirus (HPV) types 16 and 18 are limited. A type-stratified set of infections by non-HPV16/18 oncogenic types that were detected at ≥2 visits was randomly selected from women who were enrolled in a clinical trial and followed every 6 months for 2 years for detection of HPV and cervical intraepithelial neoplasia grades 2 and 3 (CIN2/3). Type-specific viral load was measured on both first and last HPV-positive cervical swab samples. CIN2/3 was initially confirmed at the last HPV-positive visit for 67 of 439 infections. The increase in risk of CIN2/3 was associated with high, relative to low, viral load at both first and last positive visits [ORadjusted = 3.67; 95% confidence interval (CI), 1.19-11.32] and marginally associated with a change of viral load from low to high levels (ORadjusted = 3.15; 95% CI, 0.96-10.35) for infection by species group alpha-9 non-HPV16 oncogenic types but not species group alpha-5-7 non-HPV18 oncogenic types. Among women with an initial diagnosis of CIN2/3 at the first positive visit, CIN2/3 was more frequently redetected at the last positive visit for infections with, compared with without, high DNA load of species group alpha-9 non-HPV16 oncogenic types at both visits (P exact = 0.04). In agreement with data on baseline viral load, the viral load change-associated risk of CIN2/3 differs by HPV species groups. These findings underscore the importance of distinguishing species groups in future studies of clinical relevance of HPV DNA load.

Virologic Suppression in U.S. Navy Personnel Living with HIV Infection and Serving in Operational Assignments.

Current United States Navy policy supports the continuation of duty for active duty (AD) service members living with HIV infection. The creation of this policy is instrumental to prevent exclusion and to promote career expansion and promotional opportunities for AD service members infected with HIV. The established instruction parallels the HIV care continuum, a widely accepted public health model. No studies have been done to determine whether allowing service members to fill operational and Outside the Continental United States (OCONUS) assignments disrupts this continuum of care. This retrospective study aims to evaluate how an operational or OCONUS assignment impacts the ability of an HIV AD service members to receive the standard of care HIV medical treatment and maintain viral suppression. A retrospective chart review was performed on the health records of 20 United States AD Navy service members with HIV who were placed in OCONUS or large ship assignments per current U.S. Navy policy. Health records were reviewed during the service member's assignment. Viral loads were documented immediately prior and at 6 months after starting their new assignment. Changes to anti-retroviral medications and the medical treatment facility, including the specialty of the treating provider were recorded. The results demonstrate no significant change in the service member's viral load during the first 6 months in an operational or OCONUS assignment. Members still had access to care including medications and specialty providers based on the locality. All service members within this review were able to maintain viral suppression despite the location of their assignments. This limited study suggests that care is accessible and the standard HIV care continuum is maintained while deployed or stationed overseas.

Antibody-dependent enhancement of influenza disease promoted by increase in hemagglutinin stem flexibility and virus fusion kinetics

Several next-generation (universal) influenza vaccines and broadly neutralizing antibodies (bNAbs) are in clinical development. Some of these mediate inhibitions of virus replication at the postentry stage or use Fc-dependent mechanisms. Nonneutralizing antibodies have the potential to mediate enhancement of viral infection or disease. In the current study, two monoclonal antibodies (MAbs) 72/8 and 69/1, enhanced respiratory disease (ERD) in mice following H3N2 virus challenge by demonstrating increased lung pathology and changes in lung cytokine/chemokine levels. MAb 78/2 caused changes in the lung viral loads in a dose-dependent manner. Both MAbs increased HA sensitivity to trypsin cleavage at a higher pH range, suggesting MAb-induced conformational changes. pHrodo-labeled virus particles' entry and residence time in the endocytic compartment were tracked during infection of Madin-Darby canine kidney (MDCK) cells. Both MAbs reduced H3N2 virus residence time in the endocytic pathway, suggesting faster virus fusion kinetics. Structurally, 78/2 and 69/1 Fabs bound the globular head or base of the head domain of influenza hemagglutinin (HA), respectively, and induced destabilization of the HA stem domain. Together, this study describes Mab-induced destabilization of the influenza HA stem domain, faster kinetics of influenza virus fusion, and ERD in vivo. The in vivo animal model and in vitro assays described could augment preclinical safety evaluation of antibodies and next-generation influenza vaccines that generate antibodies which do not block influenza virus-receptor interaction.

Felis catus papillomavirus type 2 virus-like particle vaccine is safe and immunogenic but does not reduce FcaPV-2 viral loads in adult cats

Felis catus papillomavirus type 2 (FcaPV-2) commonly infects the skin of domestic cats and has been associated with the development of skin cancer. In the present study, a FcaPV-2 virus-like particle (VLP) vaccine was produced and assessed for vaccine safety, immunogenicity, and impact on FcaPV-2 viral load. This is the first report of the use of a papillomavirus VLP vaccine in domestic cats. The FcaPV-2 VLP vaccine was given to ten adult cats that were naturally infected with FcaPV-2, and a further ten naturally infected cats were sham vaccinated as a control group. The rationale for vaccinating cats already infected with the virus was to induce neutralizing antibody titers that could prevent reinfection of new areas of skin and reduce the overall viral load, as has been demonstrated in other species. Reducing the overall FcaPV-2 viral load could reduce the risk for subsequent PV-associated cancer. The vaccine in this study was well-tolerated, as none of the cats developed any signs of local reaction or systemic illness. In the treatment group, the geometric mean anti-papillomavirus endpoint antibody titers increased significantly following vaccination from 606 (95% CI 192–1913) to 4223 (2023–8814), a 7.0-fold increase, although the individual antibody response varied depending on the level of pre-existing antibodies. Despite the immunogenicity of the vaccine, there was no significant change in FcaPV-2 viral load in the treatment group compared to the control group, over the 24 week follow-up period. A possible reason is that FcaPV-2 was already widespread in the basal skin layer of these adult cats and so preventing further cells from becoming infected had no impact on the overall viral load. Therefore, these results do not support the use of a FcaPV-2 VLP vaccine to reduce the risk for PV-associated cancer in cats in which FcaPV-2 infection is already well established. However, these results justify future studies in which the vaccine is administered to younger cats prior to FcaPV-2 infection becoming fully established.