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1.
Nature ; 606(7913): 375-381, 2022 06.
Article in English | MEDLINE | ID: covidwho-1890198

ABSTRACT

Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV)1. However, eradication of the virus in individuals with HIV has not been possible to date2. 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 replication3. 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.


Subject(s)
Anti-HIV Agents , Antibodies, Neutralizing , HIV Antibodies , HIV Infections , HIV-1 , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/adverse effects , Anti-HIV Agents/immunology , Anti-HIV Agents/therapeutic use , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/adverse effects , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/therapeutic use , Broadly Neutralizing Antibodies/administration & dosage , Broadly Neutralizing Antibodies/adverse effects , Broadly Neutralizing Antibodies/immunology , Broadly Neutralizing Antibodies/therapeutic use , Double-Blind Method , HIV Antibodies/administration & dosage , HIV Antibodies/adverse effects , HIV Antibodies/immunology , HIV Antibodies/therapeutic use , HIV Infections/drug therapy , HIV Infections/immunology , HIV Infections/virology , HIV-1/drug effects , HIV-1/immunology , HIV-1/isolation & purification , Humans , Viral Load/drug effects , Viremia/drug therapy , Viremia/immunology , Viremia/virology
2.
Viruses ; 14(6)2022 06 03.
Article in English | MEDLINE | ID: covidwho-1884380

ABSTRACT

In South Africa, high exposure to SARS-CoV-2 occurs primarily in densely populated, low-income communities, which are additionally burdened by highly prevalent Human Immunodeficiency Virus (HIV). With the aim to assess SARS-CoV-2 seroprevalence and its association with HIV-related clinical parameters in non-hospitalized patients likely to be highly exposed to SARS-CoV-2, this observational cross-sectional study was conducted at the Gugulethu Community Health Centre Antiretroviral clinic between October 2020 and June 2021, after the first COVID-19 wave in South Africa and during the second and beginning of the third wave. A total of 150 adult (median age 39 years [range 20-65 years]) HIV-infected patients (69% female; 31% male) were recruited. 95.3% of the cohort was on antiretroviral therapy (ART), had a median CD4 count of 220 cells/µL (range 17-604 cells/µL) and a median HIV viral load (VL) of 49 copies/mL (range 1-1,050,867 copies/mL). Furthermore, 106 patients (70.7%) were SARS-CoV-2 seropositive, and 0% were vaccinated. When stratified for HIV VL, patients with uncontrolled HIV viremia (HIV VL > 1000 copies/mL) had significantly higher odds of SARS-CoV-2 seropositivity than patients with HIV VL < 1000 copies/mL, after adjusting for age, sex and ART status (p = 0.035, adjusted OR 2.961 [95% CI: 1.078-8.133]). Although the cause-effect relationship could not be determined due to the cross-sectional study design, these results point towards a higher risk of SARS-CoV-2 susceptibility among viremic HIV patients, or impaired HIV viral control due to previous co-infection with SARS-CoV-2.


Subject(s)
COVID-19 , HIV Infections , Adult , Aged , CD4 Lymphocyte Count , COVID-19/epidemiology , Cross-Sectional Studies , Female , HIV Infections/complications , HIV Infections/drug therapy , HIV Infections/epidemiology , Humans , Male , Middle Aged , SARS-CoV-2 , Seroepidemiologic Studies , South Africa/epidemiology , Viral Load , Viremia/drug therapy , Viremia/epidemiology , Young Adult
3.
J Clin Virol ; 150-151: 105159, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1851455

ABSTRACT

BACKGROUND: Chronic hepatitis B virus (HBV) treatment consists of nucleos(t)ide analogues to suppress viral replication. The HBV inhibitor tenofovir has a high barrier to resistance, however, evidence of virus-escape is emerging. This study investigates HBV evolution in patients undergoing tenofovir treatment with the primary aim to assess the emergence of putative resistance mutations. METHODS: HBV DNA was extracted from blood samples of two patients with HBeAg-positive chronic HBV infection and persistent viremia despite tenofovir treatment, and subsequently amplified by PCR before full-length HBV genomes were assembled by deep sequencing. The mutation linkage within the viral population was evaluated by clonal analysis of amplicons. RESULTS: Sequence analysis of HBV, derived from 11 samples collected 2010-2020 from one patient, identified 12 non-synonymous single-nucleotide polymorphisms (SNPs) emerging during a tenofovir treatment interruption from 2014 to 2017. Two of the SNPs were in the reverse transcriptase (RT; H35Q and D263E). The two RT mutations were linked and persisted despite restarting tenofovir treatment in 2017. For the second patient, we analyzed HBV derived from six samples collected 2014-2020 following 10 years of tenofovir treatment, and identified five non-synonymous SNPs, that confer resistance towards entecavir and/or lamivudine. Two RT mutations (H35N and P237T) emerged during subsequent 5-year entecavir treatment. H35N was maintained during final tenofovir treatment. CONCLUSIONS: Our findings indicate that changes at the conserved residue 35 (H35N/Q) in the HBV RT may be associated with tenofovir resistance. These variants have not previously been described, and further studies are warranted to assess resistance in vitro and in vivo.


Subject(s)
Hepatitis B, Chronic , Organophosphonates , Adenine/adverse effects , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , DNA, Viral/genetics , Drug Resistance, Viral/genetics , Hepatitis B virus/genetics , Hepatitis B, Chronic/drug therapy , Humans , Mutation , Organophosphonates/therapeutic use , RNA-Directed DNA Polymerase/genetics , Tenofovir/pharmacology , Tenofovir/therapeutic use , Viremia/drug therapy
4.
Front Immunol ; 12: 784145, 2021.
Article in English | MEDLINE | ID: covidwho-1674332

ABSTRACT

As the coronavirus disease 2019 (COVID-19) pandemic is ongoing and new variants of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are emerging, there is an urgent need for vaccines to protect individuals at high risk for complications and to potentially control disease outbreaks by herd immunity. Surveillance of rare safety issues related to these vaccines is progressing, since more granular data emerge about adverse events of SARS-CoV-2 vaccines during post-marketing surveillance. Varicella zoster virus (VZV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivation has already been reported in COVID-19 patients. In addition, adverse events after SARS-CoV-2 mRNA vaccination have also been in the context of varicella zoster virus (VZV) reactivation and directly associated with the mRNA vaccine. We present the first case of CMV reactivation and pericarditis in temporal association with SARS-CoV-2 vaccination, particularly adenovirus-based DNA vector vaccine ChAdOx1 nCoV-19 against SARS-CoV-2. After initiation of antiviral therapy with oral valganciclovir, CMV viremia disappeared and clinical symptoms rapidly improved. Since huge vaccination programs are ongoing worldwide, post-marketing surveillance systems must be in place to assess vaccine safety that is important for the detection of any events. In the context of the hundreds of millions of individuals to be vaccinated against SARS-CoV-2, a potential causal association with CMV reactivation may result in a considerable number of cases with potentially severe complications.


Subject(s)
/adverse effects , Cytomegalovirus/drug effects , Pericarditis/chemically induced , SARS-CoV-2/immunology , Virus Activation/drug effects , Aged , Antiviral Agents/therapeutic use , COVID-19/prevention & control , Cytomegalovirus/physiology , Cytomegalovirus Infections/chemically induced , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/virology , Female , Humans , Pericarditis/drug therapy , Pericarditis/virology , Treatment Outcome , Valganciclovir/therapeutic use , Viremia/chemically induced , Viremia/drug therapy , Viremia/virology
5.
J Infect Dis ; 225(5): 856-861, 2022 Mar 02.
Article in English | MEDLINE | ID: covidwho-1666006

ABSTRACT

We tested the combination of a broadly neutralizing HIV antibody with the latency reversal agent vorinostat (VOR). Eight participants received 2 month-long cycles of VRC07-523LS with VOR. Low-level viremia, resting CD4+ T-cell-associated HIV RNA (rca-RNA) was measured, and intact proviral DNA assay (IPDA) and quantitative viral outgrowth assay (QVOA) were performed at baseline and posttreatment. In 3 participants, IPDA and QVOA declines were accompanied by significant declines of rca-RNA. However, no IPDA or QVOA declines clearly exceeded assay variance or natural decay. Increased resistance to VRC07-523LS was not observed. This combination therapy did not reduce viremia or the HIV reservoir. Clinical Trials Registration. NCT03803605.


Subject(s)
HIV Infections , HIV-1 , Broadly Neutralizing Antibodies , CD4-Positive T-Lymphocytes , HIV-1/genetics , Humans , Viremia/drug therapy , Virus Latency , Vorinostat/therapeutic use
6.
Sci Rep ; 11(1): 19458, 2021 09 30.
Article in English | MEDLINE | ID: covidwho-1447326

ABSTRACT

Efficacious therapeutics for Ebola virus disease are in great demand. Ebola virus infections mediated by mucosal exposure, and aerosolization in particular, present a novel challenge due to nontypical massive early infection of respiratory lymphoid tissues. We performed a randomized and blinded study to compare outcomes from vehicle-treated and remdesivir-treated rhesus monkeys in a lethal model of infection resulting from aerosolized Ebola virus exposure. Remdesivir treatment initiated 4 days after exposure was associated with a significant survival benefit, significant reduction in serum viral titer, and improvements in clinical pathology biomarker levels and lung histology compared to vehicle treatment. These observations indicate that remdesivir may have value in countering aerosol-induced Ebola virus disease.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , Ebolavirus/drug effects , Hemorrhagic Fever, Ebola/drug therapy , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/pharmacology , Administration, Intravenous , Aerosols , Alanine/administration & dosage , Alanine/pharmacology , Animals , Antiviral Agents/administration & dosage , Disease Models, Animal , Female , Hemorrhagic Fever, Ebola/blood , Kaplan-Meier Estimate , Liver/drug effects , Liver/virology , Lung/pathology , Lung/virology , Lymph Nodes/drug effects , Lymph Nodes/pathology , Lymph Nodes/virology , Macaca mulatta , Male , Random Allocation , Systemic Inflammatory Response Syndrome/drug therapy , Systemic Inflammatory Response Syndrome/virology , Viral Load/drug effects , Viremia/drug therapy
7.
PLoS One ; 16(7): e0254167, 2021.
Article in English | MEDLINE | ID: covidwho-1295525

ABSTRACT

Dexamethasone provides benefits in patients with coronavirus disease 2019 (COVID-19), although data regarding immunological profiles and viral clearance are limited. This study aimed to evaluate for differences in biomarkers among patients with severe COVID-19 who did and did not receive dexamethasone. We measured plasma biomarkers of lung epithelial/endothelial injury and inflammation in 31 patients with severe COVID-19 and in 13 controls. Changes in biomarkers and clinical parameters were compared during the 7-day period among COVID-19 patients, and also according to dexamethasone use. Thirty-two patients with severe COVID-19 who received mechanical ventilation (n = 6), high-flow nasal cannula (n = 11), and supplemental oxygen (n = 15) were analyzed. Relative to controls, patients with severe COVID-19 had significantly higher concentrations of biomarkers related to glycocalyx shedding (endocan and syndecan-1), endothelial injury (von Willebrand factor), and inflammation (soluble receptor for advanced glycation end-products [sRAGE] and interleukin-6). The 7-day decreases in biomarkers of endothelial injury (angiopoietin-2 [Ang-2] and intercellular adhesion molecule-1 [ICAM-1]) and sRAGE, but not in the biomarker of lung epithelial injury (surfactant protein D), were correlated with decreases in C-reactive protein and radiologic score at day 7. Twenty patients (63%) received dexamethasone, and the dexamethasone and non-dexamethasone groups differed in terms of disease severity. However, dexamethasone was associated marginally with increased SpO2/FiO2 and significantly with decreases in C-reactive protein and radiologic score after adjusting for baseline imbalances. Furthermore, the dexamethasone group exhibited a significant decrease in the concentrations of Ang-2, ICAM-1, soluble form of the Tie2 receptor (a biomarker of glycocalyx shedding), and sRAGE. Both groups exhibited a clinically insignificant increase in the cycle threshold value. Severe COVID-19 may be characterized by more severe endothelial injury and inflammation, and less severe lung epithelial injury. There is a possibility that dexamethasone improved severe COVID-19 and related endothelial injury without delaying viral clearance.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Dexamethasone/therapeutic use , Endothelium, Vascular/drug effects , Inflammation/prevention & control , SARS-CoV-2 , Viremia/drug therapy , Adult , Aged , Anti-Inflammatory Agents/pharmacology , Biomarkers , COVID-19/blood , COVID-19/diagnostic imaging , Dexamethasone/pharmacology , Endothelium, Vascular/pathology , Female , Humans , Inflammation/blood , Inflammation/etiology , Lung Injury/blood , Lung Injury/diagnostic imaging , Lung Injury/etiology , Male , Oxygen/blood , Pilot Projects , Viral Load , Viremia/blood
8.
Viruses ; 13(6)2021 06 12.
Article in English | MEDLINE | ID: covidwho-1282640

ABSTRACT

There is a growing number of perinatally HIV-1-infected children worldwide who must maintain life-long ART. In early life, HIV-1 infection is established in an immunologically inexperienced environment in which maternal ART and immune dynamics during pregnancy play a role in reservoir establishment. Children that initiated early antiretroviral therapy (ART) and maintained long-term suppression of viremia have smaller and less diverse HIV reservoirs than adults, although their proviral landscape during ART is reported to be similar to that of adults. The ability of these early infected cells to persist long-term through clonal expansion poses a major barrier to finding a cure. Furthermore, the effects of life-long HIV persistence and ART are yet to be understood, but growing evidence suggests that these individuals are at an increased risk for developing non-AIDS-related comorbidities, which underscores the need for an HIV cure.


Subject(s)
Anti-Retroviral Agents/therapeutic use , Antiretroviral Therapy, Highly Active , Disease Reservoirs/virology , HIV Infections/virology , HIV-1/pathogenicity , Child , DNA, Viral/genetics , Female , HIV-1/genetics , Humans , Infectious Disease Transmission, Vertical , Pregnancy , Proviruses/genetics , Viral Load , Viremia/drug therapy
9.
BMJ Case Rep ; 14(2)2021 Feb 04.
Article in English | MEDLINE | ID: covidwho-1066845

ABSTRACT

COVID-19 is a biphasic illness with an initial viraemia phase and later effective adaptive immune phase, except in a minority of people who develop severe disease. Immune regulation is the key target to treat COVID illness. In anticipation, an elderly man self-medicated himself with dexamethasone on the day of symptom onset of a flu-like illness, took other symptomatic measures and was tested positive for SARS-CoV-2. His condition deteriorated with each passing day resulting in hospitalisation. He demanded oxygen and declared as severe COVID. With supportive treatment, he recovered after the 20th day of illness. Immunosuppression and anti-inflammation are likely to benefit when the immune response is dysregulated and turning into a cytokine storm. A medication that has saved many could be the one predisposing to severity if taken as a preventive measure, too early in the disease course, especially the viraemia phase.


Subject(s)
Anti-Inflammatory Agents/adverse effects , COVID-19/drug therapy , Dexamethasone/adverse effects , Viremia/drug therapy , Aged , Anti-Infective Agents/therapeutic use , Anti-Inflammatory Agents/therapeutic use , COVID-19/complications , Dexamethasone/therapeutic use , Hospitalization , Humans , Hydroxychloroquine/therapeutic use , Male , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , SARS-CoV-2/isolation & purification , Self Medication/methods , Steroids/adverse effects , Steroids/therapeutic use , Treatment Outcome , Viremia/complications
10.
N Engl J Med ; 383(5): 452-459, 2020 07 30.
Article in English | MEDLINE | ID: covidwho-692294

ABSTRACT

BACKGROUND: Insufficient vaccine doses and the lack of therapeutic agents for yellow fever put global health at risk, should this virus emerge from sub-Saharan Africa and South America. METHODS: In phase 1a of this clinical trial, we assessed the safety, side-effect profile, and pharmacokinetics of TY014, a fully human IgG1 anti-yellow fever virus monoclonal antibody. In a double-blind, phase 1b clinical trial, we assessed the efficacy of TY014, as compared with placebo, in abrogating viremia related to the administration of live yellow fever vaccine (YF17D-204; Stamaril). The primary safety outcomes were adverse events reported 1 hour after the infusion and throughout the trial. The primary efficacy outcome was the dose of TY014 at which 100% of the participants tested negative for viremia within 48 hours after infusion. RESULTS: A total of 27 healthy participants were enrolled in phase 1a, and 10 participants in phase 1b. During phase 1a, TY014 dose escalation to a maximum of 20 mg per kilogram of body weight occurred in 22 participants. During phases 1a and 1b, adverse events within 1 hour after infusion occurred in 1 of 27 participants who received TY014 and in none of the 10 participants who received placebo. At least one adverse event occurred during the trial in 22 participants who received TY014 and in 8 who received placebo. The mean half-life of TY014 was approximately 12.8 days. At 48 hours after the infusion, none of the 5 participants who received the starting dose of TY014 of 2 mg per kilogram had detectable YF17D-204 viremia; these participants remained aviremic throughout the trial. Viremia was observed at 48 hours after the infusion in 2 of 5 participants who received placebo and at 72 hours in 2 more placebo recipients. Symptoms associated with yellow fever vaccine were less frequent in the TY014 group than in the placebo group. CONCLUSIONS: This phase 1 trial of TY014 did not identify worrisome safety signals and suggested potential clinical benefit, which requires further assessment in a phase 2 trial. (Funded by Tysana; ClinicalTrials.gov number, NCT03776786.).


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Yellow Fever Vaccine , Yellow Fever/drug therapy , Yellow fever virus/immunology , Adult , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacokinetics , Dose-Response Relationship, Drug , Double-Blind Method , Half-Life , Humans , Kaplan-Meier Estimate , Viremia/drug therapy , Yellow Fever/virology , Yellow fever virus/drug effects
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