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A phase 2b study to evaluate the safety and efficacy of VRC01 broadly neutralizing monoclonal antibody in reducing acquisition of HIV-1 infection in women in sub-Saharan Africa: baseline findings

J Acquir Immune Defic Syndr

2021 Kagisho Baepanye; Larry Corey; Michal Juraska; Erika Rudnicki; Carissa Karg; Nandisile Luthuli; Maurine Miner; Maija Anderson; John Hural; Michelle Karuna; Nidhi Kochar; India Tindale; Deborah Donnell; Kyle Marshall; Simbarashe Takuva

BACKGROUND: HIV Vaccine Trials Network (HVTN) 703/HIV Prevention Trials Network (HPTN) 081 is a phase 2b randomized, double-blind placebo-controlled trial to assess the safety and efficacy of passively infused monoclonal antibody (mAb) VRC01 in preventing HIV acquisition in heterosexual women between the ages of 18 and 50 at risk of HIV. Participants were enrolled at 20 sites in Botswana, Kenya, Malawi, Mozambique, South Africa, Tanzania and Zimbabwe. It is one of two Antibody Mediated Prevention (AMP) efficacy trials, with HVTN 704/HPTN 085, evaluating VRC01 for HIV prevention. METHODS: Intense community engagement was utilized to optimize participant recruitment and retention. Participants were randomly assigned to receive intravenous (IV) VRC01 10 mg/kg, VRC01 30 mg/kg, or placebo in a 1:1:1 ratio. Infusions were given every eight weeks with a total of 10 infusions and 104 weeks of follow-up after the first infusion. RESULTS: Between May 2016 and September 2018, 1924 women from sub-Saharan Africa were enrolled. The median age was 26 (IQR: 22-30) and 98.9% were Black. Sexually transmitted infection prevalence at enrollment included chlamydia (16.9%), trichomonas (7.2%), gonorrhea (5.7%) and syphilis (2.2%). External condoms (83.2%) and injectable contraceptives (61.1%) were the methods of contraception most frequently used by participants. In total, through April 3, 2020, 38,490 clinic visits were completed with a retention rate of 96% and 16,807 infusions administered with an adherence rate of 98%. CONCLUSIONS: This proof-of-concept, large-scale mAb study demonstrates the feasibility of conducting complex trials involving IV infusions in high-incidence populations in sub-Saharan Africa.

Feasibility and Successful Enrollment in a Proof-of-Concept HIV Prevention Trial of VRC01, a Broadly Neutralizing HIV-1 Monoclonal Antibody

J Acquir Immune Defic Syndr

2021 Maija Anderson; Gail Broder; India Tindale; Allan DeCamp; Peter Gilbert; John Hural; Carissa Karg; Michelle Karuna; Larry Corey; Maurine Miner; Robert De La Grecca; Nidhi Kochar; Erika Rudnicki

BACKGROUND: The Antibody Mediated Prevention (AMP) trials (HVTN 704/HPTN 085 & HVTN 703/HPTN 081) are the first efficacy trials to evaluate whether VRC01, a broadly neutralizing monoclonal antibody (mAb) targeting the CD4 binding site of the HIV envelope protein, prevents sexual transmission of HIV-1. HVTN 704/HPTN 085 enrolled 2,701 cisgender men and transgender (TG) individuals who have sex with men at 26 sites in Brazil, Peru, Switzerland and the United States. METHODS: Participants were recruited and retained through early, extensive community engagement. Eligible participants were randomized 1:1:1 to 10 mg/kg or 30 mg/kg of VRC01 or saline placebo. Visits occurred monthly, with intravenous (IV) infusions every 8 weeks over 2 years, for a total of ten infusions. Participants were followed for 104 weeks after first infusion. RESULTS: The median HVTN 704/HPTN 085 participant age was 28; 99% were assigned male sex; 90% identified as cisgender male, 5% as TG female and the remaining as other genders. Thirty-two percent were White, 15% Black and 57% Hispanic/Latinx. Twenty-eight percent had a sexually transmitted infection at enrollment. Over 23,000 infusions were administered with no serious IV administration complications. Overall retention and adherence to the study schedule exceeded 90%, and the drop-out rate was below 10% annually (7.3 per 100-person years) through Week 80, the last visit for the primary endpoint. CONCLUSIONS: HVTN 704/HPTN 085 exceeded accrual and retention expectations. With exceptional safety of IV administration and operational feasibility, it paves the way for future large-scale mAb trials for HIV prevention and/or treatment.

Evaluating Specimen Quality and Results from a Community-Wide, Home-Based Respiratory Surveillance Study

J Clin Microbiol

2021 Jover Lee; Trevor Bedford; Michael Boeckh; Janet Englund; Debbie Nickerson; Mikaela Ilcisin; Thomas Sibley; Matthew Thompson; Kairsten Fay; Lea Starita

Introduction. While influenza and other respiratory pathogens cause significant morbidity and mortality, the community-based burden of these infections remains incompletely understood. The development of novel methods to detect respiratory infections is essential for mitigating epidemics and developing pandemic-preparedness infrastructure.Methods. From October 2019 to March 2020, we conducted a home-based cross-sectional study in the greater Seattle area, utilizing electronic consent and data collection instruments. Participants received nasal swab collection kits via rapid delivery within 24 hours of self-reporting respiratory symptoms. Samples were returned to the laboratory and were screened for 26 respiratory pathogens and a housekeeping gene. Participant data were recorded via online survey at the time of sample collection and one week later.Results. Of the 4,572 consented participants, 4,359 (95.3%) received a home swab kit, and 3,648 (83.7%) returned a nasal specimen for respiratory pathogen screening. The 3,638 testable samples had a mean RNase P CRT value of 19.0 (SD: 3.4) and 1,232 (33.9%) samples had positive results for one or more pathogens, including 645 (17.7%) influenza-positive specimens. Among the testable samples, the median time between shipment of the home swab kit and completion of laboratory testing was 8 days [IQR: 7.0-14.0]. A single adverse event occurred and did not cause long-term effects or require medical attention.Discussion. Home-based surveillance using online participant enrollment and specimen self-collection is a safe and feasible method for community-level monitoring of influenza and other respiratory pathogens, which can readily be adapted for use during pandemics.

Safety, uptake, and use of a dapivirine vaginal ring for HIV-1 prevention in African women (HOPE): an open-label, extension study

Lancet HIV

2021 Melissa Peda; Daniel Szydlo; Karen Patterson; Elizabeth Brown; Yuqing Jiao

BACKGROUND: Two phase 3 clinical trials showed that use of a monthly vaginal ring containing 25 mg dapivirine was well tolerated and reduced HIV-1 incidence in women by approximately 30% compared with placebo. We aimed to evaluate use and safety of the dapivirine vaginal ring (DVR) in open-label settings with high background rates of HIV-1 infection, an important step for future implementation. METHODS: We did a phase 3B open-label extension trial of the DVR (MTN-025/HIV Open-label Prevention Extension [HOPE]). Women who were HIV-1-negative and had participated in the MTN-020/ASPIRE phase 3 trial were offered 12 months of access to the DVR at 14 clinical research centres in Malawi, South Africa, Uganda, and Zimbabwe. At each visit (monthly for 3 months, then once every 3 months), women chose whether or not to accept the offer of the ring. Used, returned rings were tested for residual amounts of dapivirine as a surrogate marker for adherence. HIV-1 serological testing was done at each visit. Dapivirine amounts in returned rings and HIV-1 incidence were compared with data from the ASPIRE trial, and safety was assessed. This study is registered with, NCT02858037. FINDINGS: Between July 16, 2016, and Oct 10, 2018, of 1756 women assessed for eligibility, 1456 were enrolled and participated in the study. Median age was 31 years (IQR 27-37). At baseline, 1342 (922%) women chose to take the DVR; ring acceptance was more than 79% at each visit up until 12 months and 936 (732%) of 1279 chose to take the ring at all visits. 12530 (893%) of 14034 returned rings had residual dapivirine amounts consistent with some use during the previous month (>09 mg released) and the mean dapivirine amount released was greater than in the ASPIRE trial (by 021 mg; p<00001). HIV-1 incidence was 27 per 100 person-years (95% CI 19-38, 35 infections), compared with an expected incidence of 44 per 100 person-years (32-58) among a population matched on age, site, and presence of a sexually transmitted infection from the placebo group of ASPIRE. No serious adverse events or grade 3 or higher adverse events observed were assessed as related to the DVR. INTERPRETATION: High uptake and persistent use in this open-label extension study support the DVR as an HIV-1 prevention option for women. With an increasing number of HIV-1 prophylaxis choices on the horizon, these results suggest that the DVR will be an acceptable and practical option for women in Africa. FUNDING: The Microbicide Trials Network and the National Institute of Allergy and Infectious Diseases, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health, all components of the US National Institutes of Health.

Urine Tenofovir Levels Measured Using a Novel Immunoassay Predict Human Immunodeficiency Virus Protection

Clin Infect Dis

2021 Nelly Mugo; Deborah Donnell

New tools are needed to support pre-exposure prophylaxis (PrEP) adherence for human immunodeficiency virus (HIV) prevention, including those that enable real-time feedback. In a large, completed PrEP trial, adequate urine tenofovir levels measured using a novel immunoassay predicted HIV protection and showed good sensitivity and specificity for detectable plasma tenofovir.

Pharmacokinetics and predicted neutralisation coverage of VRC01 in HIV-uninfected participants of the Antibody Mediated Prevention (AMP) trials


2021 Yunda Huang; Allan DeCamp; Peter Gilbert; Erika Rudnicki; Larry Corey; April Randhawa; Yuanyuan Zhang; Michal Juraska; Lindsay Carpp; Michelle Karuna

The phase 2b AMP trials are testing whether the broadly neutralising antibody VRC01 prevents HIV-1 infection in two cohorts: women in sub-Saharan Africa, and men and transgender persons who have sex with men (MSM/TG) in the Americas and Switzerland. We used nonlinear mixed effects modelling of longitudinal serum VRC01 concentrations to characterise pharmacokinetics and predict HIV-1 neutralisation coverage. We found that body weight significantly influenced clearance, and that the mean peripheral volume of distribution, steady state volume of distribution, elimination half-life, and accumulation ratio were significantly higher in MSM/TG than in women. Neutralisation coverage was predicted to be higher in the first (versus second) half of a given 8-week infusion interval, and appeared to be higher in MSM/TG than in women overall. Study cohort differences in pharmacokinetics and neutralisation coverage provide insights for interpreting the AMP results and for investigating how VRC01 concentration and neutralisation correlate with HIV incidence.

Evidence for adaptive evolution in the receptor-binding domain of seasonal coronaviruses OC43 and 229E


2021 Trevor Bedford

Seasonal coronaviruses (OC43, 229E, NL63 and HKU1) are endemic to the human population, regularly infecting and reinfecting humans while typically causing asymptomatic to mild respiratory infections. It is not known to what extent reinfection by these viruses is due to waning immune memory or antigenic drift of the viruses. Here, we address the influence of antigenic drift on immune evasion of seasonal coronaviruses. We provide evidence that at least two of these viruses, OC43 and 229E, are undergoing adaptive evolution in regions of the viral spike protein that are exposed to human humoral immunity. This suggests that reinfection may be due, in part, to positively-selected genetic changes in these viruses that enable them to escape recognition by the immune system. It is possible that, as with seasonal influenza, these adaptive changes in antigenic regions of the virus would necessitate continual reformulation of a vaccine made against them.

Spatially Weighted Coronary Artery Calcium Score and Coronary Heart Disease Events in the Multi-Ethnic Study of Atherosclerosis

Circ Cardiovasc Imaging

2021 Elizabeth Brown

BACKGROUND: A limitation of the Agatston coronary artery calcium (CAC) score is that it does not use all of the calcium density information in the computed tomography scan such that many individuals have a score of zero. We examined the predictive validity for incident coronary heart disease (CHD) events of the spatially weighted coronary calcium score (SWCS), an alternative scoring method for CAC that assigns scores to individuals with Agatston CAC=0. METHODS: The MESA (Multi-Ethnic Study of Atherosclerosis) is a longitudinal study that conducted a baseline exam from 2000 to 2002 in 6814 participants including computed tomography scanning for CAC. Subsequent exams and systematic follow-up of the cohort for outcomes were performed. Statistical models were adjusted using the MESA risk score based on age, sex, race/ethnicity, systolic blood pressure, use of hypertension medications, diabetes, total and HDL (high-density lipoprotein) cholesterol, use of lipid-lowering medications, smoking status, and family history of heart attack. RESULTS: In the 3286 participants with Agatston CAC=0 at baseline and for whom SWCS was computed, 98 incident CHD events defined as definite or probably myocardial infarction or definite CHD death occurred during a median follow-up of 15.1 years. In this group, SWCS predicted incident CHD events after multivariable adjustment (hazard ratio=1.30 per SD of natural logarithm [SWCS] [95% CI, 1.04-1.60]; P=0.005); and progression from Agatston CAC=0 at baseline to CAC>0 at subsequent exams (multivariable-adjusted incidence rate difference per SD of natural logarithm [SWCS] per 100 person-years 1.68 [95% CI, 1.03-2.33]; P<0.0001). CONCLUSIONS: SWCS predicts incident CHD events in individuals with Agatston CAC score=0 as well as conversion to Agatston CAC>0 at repeat computed tomography scanning at later exams. SWCS has predictive validity as a subclinical phenotype and marker of CHD risk in individuals with Agatston CAC=0.

Uptake of antiretroviral treatment and viral suppression among men who have sex with men and transgender women in sub-Saharan Africa in an observational cohort study: HPTN 075

Int J Infect Dis

2021 Ying Chen; Xu Guo

OBJECTIVES: HPTN 075 enrolled men who have sex with men (MSM) and transgender women (TGW) in sub-Saharan Africa. Persons in HIV care or on antiretroviral treatment (ART) were not eligible to enroll. We evaluated antiretroviral (ARV) drug use, viral suppression, and drug resistance in this cohort over a 12-month follow-up period. METHODS: Assessments included 64 participants with HIV (39 MSM, 24 TGW, one gender not specified). ARV drugs were detected using a qualitative assay. Viral load (VL) and drug resistance testing were performed using commercial assays. RESULTS: Over 12 months, the proportion of participants using ARV drugs increased from 28.1% to 59.4% and the proportion with VLs <400 copies/mL increased from 21.9% to 57.8%. The rate of ART failure (detection of drugs without viral suppression) was similar at screening and 12 months (12.0% and 11.1%, respectively) and was similar among MSM and TGW. Two participants developed HIV drug resistance during follow-up. CONCLUSIONS: Over 12 months, ARV drug use in the cohort more than doubled and viral suppression increased nearly three-fold without a significant increase in ART failure or drug resistance. These results suggest that ART can be successfully scaled up for HIV prevention and treatment in this high-risk population.

HIV incidence in a multinational cohort of men and transgender women who have sex with men in sub-Saharan Africa: Findings from HPTN 075

PLoS One

2021 Ying Chen; Xu Guo

Few studies have assessed HIV incidence in men who have sex with men (MSM) and transgender women (TGW) in sub-Saharan Africa (SSA). We assessed HIV incidence and its correlates among MSM and TGW in SSA enrolled in the prospective, multi-country HIV Prevention Trials Network (HPTN) 075 study, conducted from 2015 to 2017. Participants were enrolled at four sites in SSA (Kisumu, Kenya; Blantyre, Malawi; Cape Town and Soweto, South Africa). Eligible participants reported male sex assignment at birth, were 18 to 44 years of age, and had engaged in anal intercourse with a man in the preceding three months. Participation involved five study visits over 12 months. Visits included behavioral assessments and testing for HIV and sexually transmitted infections. Twenty-one of 329 persons acquired HIV during the study [incidence rate: 6.96/100 person-years (PY) (95% CI: 4.3, 10.6)]. Among TGW, HIV incidence was estimated to be 8.4/100 PY (95% CI: 2.3, 21.5). Four participants were found to have acute HIV infection at their first HIV-positive visit. HIV incidence varied among the four study sites, ranging from 1.3/100 PY to 14.4/100 PY. In multivariate longitudinal analysis, factors significantly associated with HIV acquisition were engagement in unprotected receptive anal intercourse [adjusted hazard ratio (AHR) 5.8, 95% confidence interval (CI): 2.4, 14.4] and incident rectal gonorrhea and/or chlamydia (AHR: 2.7, 95% CI: 1.1, 6.8). The higher HIV incidence in Cape Town compared to Blantyre could be explained by the higher prevalence of several risk factors for HIV infection among participants in Cape Town. Annual HIV incidence observed in this study is substantially higher than reported HIV incidence in the general populations in the respective countries and among MSM in the United States. Intensification of HIV prevention efforts for MSM and TGW in SSA is urgently needed.