Viral Load Decline Research Articles

Risk of Immune Reconstitution Inflammatory Syndrome With Integrase Inhibitors Versus Other Classes of Antiretrovirals: A Systematic Review and Meta-analysis of Randomized Trials.

BackgroundIntegrase strand transfer inhibitors (InSTIs) decrease HIV plasma viral load faster than other antiretroviral classes. More rapid viral load decline has been associated with higher risk of immune reconstitution inflammatory syndrome (IRIS). There are conflicting reports on the association between InSTI and IRIS. We performed a systematic review and meta-analysis to compare the risk of IRIS among treatment-naïve HIV-positive patients starting InSTI versus non-InSTI regimens.MethodsWe searched PubMed, Scopus, Web of Science, Africa-Wide, and Cochrane databases from earliest available date to 26 November 2021, for randomised controlled trials (RCTs) having intervention arms with InSTI versus control arms without InSTI in patients initiating first-line antiretroviral therapy. The primary outcome was relative risk (RR) of IRIS, while the secondary outcome was RR of paradoxical tuberculosis-associated IRIS (TB-IRIS). Data were combined by random-effects meta-analysis according to the Mantel-Haenszel method. The protocol for this study is registered with PROSPERO, CRD42020213976.ResultsWe included 14 RCTs comprising 8696 participants from six continents for the primary outcome of IRIS, and a subset of 674 participants (from three RCTs) for the secondary outcome of paradoxical TB-IRIS. Risk of IRIS was similar between InSTI and non-InSTI regimens (RR, 0.93, 95% confidence interval [CI], 0.75 – 1.14). There was a trend towards a lower risk of paradoxical TB-IRIS with InSTI versus efavirenz regimens that was not statistically significant (RR, 0.64, 95% CI, 0.34 – 1.19).ConclusionsIn this meta-analysis among treatment-naïve patients commencing first-line antiretroviral therapy, InSTI regimens were not associated with higher risk of IRIS.

Mucosal Antibody Response to SARS-CoV-2 in Paediatric and Adult Patients: A Longitudinal Study.

Background: SARS-CoV-2 enters the body through inhalation or self-inoculation to mucosal surfaces. The kinetics of the ocular and nasal mucosal-specific-immunoglobulin A(IgA) responses remain under-studied. Methods: Conjunctival fluid (CF, n = 140) and nasal epithelial lining fluid (NELF, n = 424) obtained by paper strips and plasma (n = 153) were collected longitudinally from SARS-CoV-2 paediatric (n = 34) and adult (n = 47) patients. The SARS-CoV-2 spike protein 1(S1)-specific mucosal antibody levels in COVID-19 patients, from hospital admission to six months post-diagnosis, were assessed. Results: The mucosal antibody was IgA-predominant. In the NELF of asymptomatic paediatric patients, S1-specific IgA was induced as early as the first four days post-diagnosis. Their plasma S1-specific IgG levels were higher than in symptomatic patients in the second week after diagnosis. The IgA and IgG levels correlated positively with the surrogate neutralization readout. The detectable NELF “receptor-blocking” S1-specific IgA in the first week after diagnosis correlated with a rapid decline in viral load. Conclusions: Early and intense nasal S1-specific IgA levels link to a rapid decrease in viral load. Our results provide insights into the role of mucosal immunity in SARS-CoV-2 exposure and protection. There may be a role of NELF IgA in the screening and diagnosis of SARS-CoV-2 infection.

Awareness and Epidemiology of Chronic Hepatitis C Virus Infections in Florida.

IntroductionProgress towards achieving hepatitis C virus (HCV) elimination in Florida has been hampered by barriers to screening, linkage to care, and treatment. This study aims to describe the HCV care cascade and patient characteristics in Florida.MethodsThis analysis combined HCV-related laboratory data and patient characteristics from two, large US laboratory datasets that included individuals tested for HCV antibody (Ab) and HCV ribonucleic acid (RNA) viral load between January 2015 and December 2019. A decline in sequential HCV RNA viral loads was used to impute HCV treatment. Machine-learning algorithms were used to identify cured patients. The actual number of individuals with HCV Ab screening, and the number and percentage of persons who were HCV RNA-positive and treated, were calculated.ResultsThe number of persons in Florida diagnosed as HCV RNA-positive was 31,659 in 2019. The number of individuals HCV Ab screened in 2019 was 1,024,379, an increase of 82.5% from 2015. The percentage of HCV Ab-positive individuals was 4.1%, demonstrating a 16.2% decrease from 2015. The percentage of HCV RNA-positive patients who were treated was 27.0%, a 10.5% decrease from 2015 to 2019.ConclusionAn Ab positivity rate > 4-times higher than national estimates with increased screening among baby boomers, but decreased screening among younger individuals, suggests risk-based screening is still common practice in Florida, despite universal screening recommendations. Public health efforts to decrease barriers to screening, linkage to care, and treatment are needed to reduce the burden of HCV in Florida and to ensure progress toward virus elimination.

Virological and serological kinetics of SARS-CoV-2 Delta variant vaccine breakthrough infections: a multicentre cohort study

ObjectivesHighly effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed but variants of concerns are worrisome, especially B.1.617.2 (Delta) which has rapidly spread across the world. We aim to study if vaccination alters virological and serological kinetics in breakthrough infections. MethodsWe conducted a multicentre retrospective cohort study of patients in Singapore who had received a licensed mRNA vaccine and been admitted to hospital with B.1.617.2 SARS-CoV-2 infection. We compared clinical features, virological and serological kinetics (anti-nucleocapsid, anti-spike and surrogate virus neutralization titres) between fully vaccinated and unvaccinated individuals. ResultsOut of 218 individuals with B.1.617.2 infection, 84 received an mRNA vaccine of which 71 were fully vaccinated, 130 were unvaccinated and four received a non-mRNA vaccine. Despite significantly older age in the vaccine breakthrough group, only 2.8% (2/71) developed severe COVID-19 requiring oxygen supplementation compared with 53.1% (69/130) in the unvaccinated group (p < 0.001). Odds of severe COVID-19 following vaccination were significantly lower (adjusted odds ratio 0.07 95% CI 0.015–0.335, p 0.001). PCR cycle threshold values were similar between vaccinated and unvaccinated groups at diagnosis, but viral loads decreased faster in vaccinated individuals. Early, robust boosting of anti-spike protein antibodies was observed in vaccinated patients; however, these titres were significantly lower against B.1.617.2 than the wildtype vaccine strain. DiscussionThe mRNA vaccines are highly effective at preventing symptomatic and severe COVID-19 associated with B.1.617.2 infection. Vaccination is associated with faster decline in viral RNA load and a robust serological response. Vaccination remains a key strategy for control of the COVID-19 pandemic.

Standard ganciclovir dosing results in slow decline of cytomegalovirus viral loads.

BackgroundCytomegalovirus (CMV) can cause severe disease, including rejection in transplant recipients. Ganciclovir and its oral prodrug valganciclovir have been used as first-line therapy for CMV disease in transplant recipients. The exposure targets of ganciclovir are not exactly known, and toxicity and resistance have interfered with ganciclovir therapy.ObjectivesTo evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of ganciclovir in transplant recipients.MethodsWe used patient data from a previous observational study on ganciclovir therapeutic drug monitoring (TDM) in prophylaxis and therapy. The ganciclovir concentrations and CMV viral loads were determined during routine clinical care. The PK/PD population modelling and simulations were done with non-parametric methodology using the Pmetrics program.ResultsEighty-five patients were included in the PK modelling. The final PK model was a two-compartment model with first-order absorption and elimination. A subset of 17 patients on CMV therapy were included in the PD modelling. A median of 4 (range 2–8) viral loads were obtained per patient. A simulation of 10 000 patients showed that an approximately 1 log10 reduction of CMV viral load will be observed after 12.5 days at the current recommended dose.ConclusionsThe developed linked PK/PD population model and subsequent PD simulations showed slow decline of CMV viral load and it appears that dosing of (val)ganciclovir in this study might have been inadequate to achieve fast reduction of viral load. It is clear that further studies are needed to specify the PD effects of ganciclovir by performing systematic measurements of both ganciclovir concentrations and CMV viral loads.

Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study

SummaryBackgroundThe SARS-CoV-2 delta (B.1.617.2) variant is highly transmissible and spreading globally, including in populations with high vaccination rates. We aimed to investigate transmission and viral load kinetics in vaccinated and unvaccinated individuals with mild delta variant infection in the community.MethodsBetween Sept 13, 2020, and Sept 15, 2021, 602 community contacts (identified via the UK contract-tracing system) of 471 UK COVID-19 index cases were recruited to the Assessment of Transmission and Contagiousness of COVID-19 in Contacts cohort study and contributed 8145 upper respiratory tract samples from daily sampling for up to 20 days. Household and non-household exposed contacts aged 5 years or older were eligible for recruitment if they could provide informed consent and agree to self-swabbing of the upper respiratory tract. We analysed transmission risk by vaccination status for 231 contacts exposed to 162 epidemiologically linked delta variant-infected index cases. We compared viral load trajectories from fully vaccinated individuals with delta infection (n=29) with unvaccinated individuals with delta (n=16), alpha (B.1.1.7; n=39), and pre-alpha (n=49) infections. Primary outcomes for the epidemiological analysis were to assess the secondary attack rate (SAR) in household contacts stratified by contact vaccination status and the index cases’ vaccination status. Primary outcomes for the viral load kinetics analysis were to detect differences in the peak viral load, viral growth rate, and viral decline rate between participants according to SARS-CoV-2 variant and vaccination status.FindingsThe SAR in household contacts exposed to the delta variant was 25% (95% CI 18–33) for fully vaccinated individuals compared with 38% (24–53) in unvaccinated individuals. The median time between second vaccine dose and study recruitment in fully vaccinated contacts was longer for infected individuals (median 101 days [IQR 74–120]) than for uninfected individuals (64 days [32–97], p=0·001). SAR among household contacts exposed to fully vaccinated index cases was similar to household contacts exposed to unvaccinated index cases (25% [95% CI 15–35] for vaccinated vs 23% [15–31] for unvaccinated). 12 (39%) of 31 infections in fully vaccinated household contacts arose from fully vaccinated epidemiologically linked index cases, further confirmed by genomic and virological analysis in three index case–contact pairs. Although peak viral load did not differ by vaccination status or variant type, it increased modestly with age (difference of 0·39 [95% credible interval –0·03 to 0·79] in peak log10 viral load per mL between those aged 10 years and 50 years). Fully vaccinated individuals with delta variant infection had a faster (posterior probability >0·84) mean rate of viral load decline (0·95 log10 copies per mL per day) than did unvaccinated individuals with pre-alpha (0·69), alpha (0·82), or delta (0·79) variant infections. Within individuals, faster viral load growth was correlated with higher peak viral load (correlation 0·42 [95% credible interval 0·13 to 0·65]) and slower decline (–0·44 [–0·67 to –0·18]).InterpretationVaccination reduces the risk of delta variant infection and accelerates viral clearance. Nonetheless, fully vaccinated individuals with breakthrough infections have peak viral load similar to unvaccinated cases and can efficiently transmit infection in household settings, including to fully vaccinated contacts. Host–virus interactions early in infection may shape the entire viral trajectory.FundingNational Institute for Health Research.

Epidemiology and Clinical Characteristics of Individuals with Hepatitis C Virus Infection in the United States, 2017-2019.

IntroductionHepatitis C virus (HCV) is the most common bloodborne chronic infection in the US. Following approval of highly effective, direct-acting antivirals in 2014, the diagnostic and treatment rates for HCV infection in the US have evolved. This study assessed the number of individuals with HCV screening or diagnostic testing and the clinical characteristics and treatment of HCV-infected individuals between 2017 and 2019.MethodsIndividuals screened for HCV antibody and/or tested for HCV ribonucleic acid (RNA) from 2017 to 2019 by two large US laboratory companies were included in this analysis. Clinical characteristics, such as HCV genotype, fibrosis stage, HIV coinfection and demographics, were assessed in HCV RNA-positive individuals. HCV treatment and subsequent achievement of sustained virologic response were imputed using data-driven algorithms based on successive viral load decline and negativity.ResultsFrom 2017 to 2019, the number of individuals tested for HCV antibody increased by 5.7%, from 7,580,303 in 2017 to 8,009,081 in 2019. The percentage of individuals tested who were HCV antibody positive was stable, ranging from 5.0% in 2017 to 4.9% in 2018 and 2019. The number of HCV RNA-positive individuals decreased by 5.0% from 382,500 in 2017 to 363,532 in 2019. Of HCV RNA-positive individuals, the proportions with genotype (GT) 3 and minimal fibrosis increased over time; proportions of individuals aged < 40 years increased, while the proportion aged 50 to 59 years decreased. Treatment rates increased from 23.4% in 2017 to 26.8% in 2019.ConclusionsThe percentage of HCV antibody-positive individuals remained stable from 2017 to 2019. The number of individuals tested HCV RNA positive decreased over the years. Demographics shifted toward a younger population with less fibrosis and higher rates of GT3. More than 70% of diagnosed individuals were not treated during this interval, highlighting a need for unfettered access to treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01928-y.

Untimely TGFβ responses in COVID-19 limit antiviral functions of NK cells.

SARS-CoV-2 is a single-stranded RNA virus that causes COVID-19. Given its acute and often self-limiting course, it is likely that components of the innate immune system play a central part in controlling virus replication and determining clinical outcome. Natural killer (NK) cells are innate lymphocytes with notable activity against a broad range of viruses, including RNA viruses1,2. NK cell function may be altered during COVID-19 despite increased representation of NK cells with an activated and adaptive phenotype3,4. Here we show that a decline in viral load in COVID-19 correlates with NK cell status and that NK cells can control SARS-CoV-2 replication by recognizing infected target cells. In severe COVID-19, NK cells show defects in virus control, cytokine production and cell-mediated cytotoxicity despite high expression of cytotoxic effector molecules. Single-cell RNA sequencing of NK cells over the time course of the COVID-19 disease spectrum reveals a distinct gene expression signature. Transcriptional networks of interferon-driven NK cell activation are superimposed by a dominant transforming growth factor-β (TGFβ) response signature, with reduced expression of genes related to cell-cell adhesion, granule exocytosis and cell-mediated cytotoxicity. In severe COVID-19, serum levels of TGFβ peak during the first two weeks of infection, and serum obtained from these patients severely inhibits NK cell function in a TGFβ-dependent manner. Our data reveal that an untimely production of TGFβ is a hallmark of severe COVID-19 and may inhibit NK cell function and early control of the virus.

Hantaviruses use the endogenous host factor P58IPK to combat the PKR antiviral response.

Hantavirus nucleocapsid protein (NP) inhibits protein kinase R (PKR) dimerization by an unknown mechanism to counteract its antiviral responses during virus infection. Here we demonstrate that NP exploits an endogenous PKR inhibitor P58IPK to inhibit PKR. The activity of P58IPK is normally restricted in cells by the formation of an inactive complex with its negative regulator Hsp40. On the other hand, PKR remains associated with the 40S ribosomal subunit, a unique strategic location that facilitates its free access to the downstream target eIF2α. Although both NP and Hsp40 bind to P58IPK, the binding affinity of NP is much stronger compared to Hsp40. P58IPK harbors an NP binding site, spanning to N-terminal TPR subdomains I and II. The Hsp40 binding site on P58IPK was mapped to the TPR subdomain II. The high affinity binding of NP to P58IPK and the overlap between NP and Hsp40 binding sites releases the P58IPK from its negative regulator by competitive inhibition. The NP-P58IPK complex is selectively recruited to the 40S ribosomal subunit by direct interaction between NP and the ribosomal protein S19 (RPS19), a structural component of the 40S ribosomal subunit. NP has distinct binding sites for P58IPK and RPS19, enabling it to serve as bridge between P58IPK and the 40S ribosomal subunit. NP mutants deficient in binding to either P58IPK or RPS19 fail to inhibit PKR, demonstrating that selective engagement of P58IPK to the 40S ribosomal subunit is required for PKR inhibition. Cells deficient in P58IPK mount a rapid PKR antiviral response and establish an antiviral state, observed by global translational shutdown and rapid decline in viral load. These studies reveal a novel viral strategy in which NP releases P58IPK from its negative regulator and selectively engages it on the 40S ribosomal subunit to promptly combat the PKR antiviral responses.

Single-dose oral ivermectin in mild and moderate COVID-19 (RIVET-COV): A single-centre randomized, placebo-controlled trial

IntroductionIvermectin is an antiparasitic drug which has in-vitro efficacy in reducing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) viral load. Hence, Ivermectin is under investigation as a repurposed agent for treating COVID-19. MethodsIn this pilot, double blind, randomized controlled trial, hospitalized patients with mild-to-moderate COVID-19 were assigned to a single oral administration of an elixir formulation of Ivermectin at either 24 mg or 12 mg dose, or placebo in a 1:1:1 ratio. The co-primary outcomes were conversion of RT-PCR to negative result and the decline of viral load at day 5 of enrolment. Safety outcomes included total and serious adverse events. The primary outcomes were assessed in patients who had positive RT-PCR at enrolment (modified intention-to-treat population). Safety outcomes were assessed in all patients who received the intervention (intention-to-treat population). ResultsAmong the 157 patients randomized, 125 were included in modified intention-to-treat analysis. 40 patients each were assigned to Ivermectin 24 mg and 12 mg, and 45 patients to placebo. The RT-PCR negativity at day 5 was higher in the two Ivermectin arms but failed to attain statistical significance (Ivermectin 24 mg, 47.5%; 12 mg arm, 35.0%; and placebo arm, 31.1%; p-value = 0.30). The decline of viral load at day 5 was similar in each arm. No serious adverse events occurred. ConclusionsIn patients with mild and moderate COVID-19, a single oral administration of Ivermectin did not significantly increase either the negativity of RT-PCR or decline in viral load at day 5 of enrolment compared with placebo.

Observation of varicella zoster virus-induced acute retinal necrosis: viral load detection and visual outcome.

To observe the changes of viral load in aqueous humour samples and visual outcomes in varicella zoster virus (VZV)-induced acute retinal necrosis (ARN). Observational retrospective study. Medical records and viral load measured by real-time quantitative polymerase chain reaction (qPCR) of 20 eyes with VZV-induced ARN were reviewed. The mean viral load at presentation was 5.7 × 107 ± 9.7 × 107 copies/mL. An initial plateau phase for viral load lasting up to 2 weeks occurred in most eyes (18 eyes, 90%). In the following logarithmic reduction phase, the mean slope of the decline in viral load was -0.103 ± 0.029 log/day, and the expected time for half reduction of the initial viral load was 3.2 ± 1.0 days. At the end of the first 8-week's antiviral treatment, the viral load was below detection threshold in all 20 eyes (100.0%). The mean logarithm of the minimum angle of resolution (logMAR) best-corrected visual acuity (BCVA) improved from 1.1 ± 0.7 (Snellen equivalent 20/250) to 0.7 ± 0.6 (Snellen equivalent 20/100) after a follow-up of 8.6 ± 2.0 months. Thirteen of the 20 eyes (65.0%) suffered retinal detachment and underwent vitrectomy. The initial viral load was the independent predictive factor of logMAR BCVA at the last follow-up (β = 0.745, P < 0.001). The observation of viral load changes by qPCR was useful for better monitoring of therapeutic efficacy and deciding needed antiviral duration in VZV-induced ARN patients.

Clinical efficacy and safety of baloxavir marboxil in the treatment of influenza: A systematic review and meta-analysis of randomized controlled trials.

The aim of this meta-analysis is to compare the clinical efficacy and safety of baloxavir with other anti-influenza agents or placebo in the treatment of influenza. PubMed, Embase, Web of Science, Google Scholar, Scopus, CINAHL, Cochrane databases and clinical registration were searched from inception until February 15 2021 for relevant randomized controlled trials (RCTs). Only phase 3 RCTs evaluating the usefulness of baloxavir in the treatment of influenza were included. Three RCTs enrolling 3771 patients (baloxavir group, n=1451; oseltamivir group, n=1288; placebo group, n=1032) were included. Compared with oseltamivir, baloxavir had an insignificantly shorter time to the alleviation of symptoms (mean difference [MD], -1.29h; 95% CI, -6.80 to 4.21; I2=0%). In contrast, baloxavir had a significantly shorter time to the alleviation of symptoms than placebo (MD, -26.32h; 95% CI, -33.78 to -18.86; I2=0%). Baloxavir was associated with a significant decline in influenza virus titers and viral RNA load compared to oseltamivir and placebo. Baloxavir was associated with a lower risk of any adverse events than oseltamivir (OR, 0.82; 95% CI, 0.69-0.98; I2=0%) and placebo (OR, 0.79; 95% CI, 0.66-0.96; I2=0%). The findings of this meta-analysis suggested that baloxavir is superior to placebo in the treatment of influenza in both clinical outcome and virological response. Moreover, baloxavir was found to have a better virological response than oseltamivir and to be as effective as oseltamivir clinically. Compared with oseltamivir and placebo, baloxavir appears to be a relatively safe anti-influenza agent.

Novel combined single dose anti-hepatitis C therapy: a pilot study

The new anti-hepatitis C virus (HCV) molecules improve treatment regimens and outcomes, but there are drawbacks. New combinations should target the HCV infectious cycle and be effective against all HCV genotypes. We developed the novel formulation Catvira, composed of epigallocatechingallate (EGCG) + sofosbuvir + ribavirin. Here, we compared Catvira to sofosbuvir + ribavirin tablets in patients with CHC genotype 4 in a randomized open-label efficacy and safety study. Treatment-naïve and treatment-experienced patients (n = 80) were randomly assigned to receive a single daily fixed dose of Catvira or sofosbuvir + ribavirin for 12 or 24 weeks. Both Catvira and sofosbuvir + ribavirin yielded similar outcomes of viral load (p < 0.001). Patients receiving Catvira had a significantly more rapid rate of viral load decline with sustained virologic response (SVR12) achieved by 90% of patients receiving 12 weeks of treatment. Catvira did not impact hemoglobin levels while sofosbuvir + ribavirin showed significant decline in hemoglobin levels after 24 weeks (p < 0.05). In this clinical trial (ClinicalTrials.gov Identifier NCT02483156), we found that Catvira administered daily for 12 or 24 weeks is safe, effective, and well-tolerated in both naïve and treatment-experienced patients with HCV genotype 4.

The within-host fitness of HIV-1 increases with age in ART-na\xefve HIV-1 subtype C infected children

As the immune system develops with age, children combat infections better. HIV-1, however, targets an activated immune system, potentially rendering children increasingly permissive to HIV-1 infection as they grow. How HIV-1 fitness changes with age in children is unknown. Here, we estimated the within-host basic reproductive ratio, R0, a marker of viral fitness, in HIV-1 subtype C-infected children in India, aged between 84 days and 17 years. We measured serial viral load and CD4 T cell counts in 171 children who initiated first-line ART. For 25 children, regular and frequent measurements provided adequate data points for analysis using a mathematical model of viral dynamics to estimate R0. For the rest, we used CD4 counts for approximate estimation of R0. The viral load decline during therapy was biphasic. The mean lifespans of productively and long-lived infected cells were 1.4 and 27.8 days, respectively. The mean R0 was 1.5 in children aged < 5 years, increased with age, and approached 6.0 at 18 years, close to 5.8 estimated previously for adults. The tolerogenic immune environment thus compromises HIV-1 fitness in young children. Early treatment initiation, when the R0 is small, will likely improve viral control, in addition to suppressing the latent reservoir.

Achieving maternal viral load suppression for elimination of mother-to-child transmission of HIV in South Africa.

To describe changes in maternal viral control over time in South African women living with HIV (WLHIV) using surveillance data from the National Health Laboratory Service's Corporate Data Warehouse (NHLS CDW). A retrospective cohort analysis of maternal viral load during pregnancy and up to 15 months postpartum was performed amongst WLHIV (15-49 years) within the public-health sector between 2016 and 2017. HIV and pregnancy-related test data were used to create a synthetic cohort of pregnant WLHIV from the NHLS CDW. Syphilis-screening, in association with ward type and/or postpregnancy cervical screening and/or birth HIV test and/or positive β-hCG, was used as a proxy for pregnancy. The syphilis-screening date marked the first antenatal care visit (fANC). Fractional polynomial models described viral load evolution from fANC up to 15 months postdelivery. Piecewise linear regression models determined factors associated with viral load decline. Among 178 319 pregnant WLHIV, 345 174 viral load tests were performed [median = 2 (IQR: 2-3) per woman]. At fANC, 85 545 (48%) women were antiretroviral therapy (ART) experienced; 88 877 (49.8%) were not and 3897 (2.2%) unknown. Proportions of viraemia (viral load ≥50 copies/ml) were 39 756 (53.6%) at first viral load performed during pregnancy, 14 780 (36.9%) at delivery and 24 328 (33.5%) postpartum. Maternal age at least 25 years, CD4+ cell count at least 500 cells/μl and viral load less than 50 copies/ml at baseline predicted sustained viral load suppression during follow-up. Despite high-ART coverage among pregnant women in South Africa, only 63% of WLHIV achieved viral load less than 50 copies/ml at delivery. Maternal viral load monitoring requires prioritization for maternal health and eMTCT.

Community Transmission and Viral Load Kinetics of SARS-CoV-2 Delta (B.1.617.2)Variant in Vaccinated and Unvaccinated Individuals

Background: The SARS-CoV-2 Delta variant is highly transmissible and spreading globally but a detailed understanding of community transmission risks in highly vaccinated populations is lacking.Methods: Between September 2020 and August 2021, we recruited 510 community contacts of 422 UK COVID-19 cases to a cohort study. A total of 7194 upper respiratory tract (URT) samples were tested from sequential daily sampling of participants for up to 20 days. We analysed transmission risk by vaccination status for 139 contacts exposed to the Delta variant. We compared viral load (VL) trajectories from fully-vaccinated cases of Delta infection (n=19) with unvaccinated Delta (n=10), Alpha (n=39) and pre-Alpha (n=49) infections.Findings: The household secondary attack rate for fully-vaccinated contacts exposed to Delta was 19.7% (95%CI:11.6-31.3%), compared with 35.7% (95%CI:16.4-61.2%) in the unvaccinated. One third of infections in Delta-exposed contacts arose from fully-vaccinated index cases and one half of infected contacts were also fully-vaccinated. Seven transmission events between fully vaccinated index-contact pairs occurred. Genomic analysis confirmed transmission pathways between fully-vaccinated individuals within three households. Peak VL was similar in vaccinated and unvaccinated individuals with Delta variant infection but vaccinated Delta cases saw significantly faster VL decline than unvaccinated Alpha or Delta cases. Within infected individuals, faster VL growth was correlated with higher peak VL and slower decline.Interpretation: Although vaccination reduces the risk of Delta infection and causes some changes to viral kinetics, fully-vaccinated individuals with breakthrough infections have peak URT VL similar to unvaccinated cases and can efficiently transmit infection in household settings, including to fully vaccinated contacts.Funding: National Institute for Health Research (Award:NIHR200927)Declaration of Interest: The authors declare no relevant conflicts.Ethical Approval: The study was approved by the Health Research Authority (Research Ethics Committee reference: 20/NW/0231).

Development and validation of a hepatitis B-specific health-related quality-of-life instrument: CLDQ-HBV.

Hepatitis B virus (HBV) carries a large global burden. Efforts abound to decrease the burden, which necessitates reporting of patient-reported outcomes (PROs). We aimed to develop and validate an HBV-specific PRO instrument using the Chronic Liver Disease Questionnaire (CLDQ). Data were obtained from patients enrolled in our HBV registries who completed the CLDQ, Short Form-36 (SF-36) and FACIT-F. The sample was split randomly 1:1 into training and testing groups. A standard PRO instrument validation pipeline was used to develop and validate the new CLDQ-HBV instrument. HBV patients (n=1,339) were 48±13years old, 60% male, 8% cirrhosis, with 53% receiving oral antivirals (OAV). After reduction of 10 redundant items, exploratory factor analysis for the remaining 19 items found 95% of variance was explained by five factors-emotional function, fatigue, systemic symptoms, worry and sleep. Good-to-excellent internal consistency was found: Cronbach's alphas 0.70-0.90 and item-to-own-domain correlations >0.50 for 18/19 items. Known-group validity tests discriminated between HBV patients with and without cirrhosis, with FIB-4≥3.25 vs <3.25, with and without history of depression or clinically overt fatigue (all p<0.0001), and treatment (all p<0.05, all but one <0.0001). After 48-week follow-up, HBV patients receiving OAV (N=144) with ≥2.7 log 10/mL decline in HBV viral load experienced significant improvements in fatigue, worry and total CLDQ-HBV scores (p<0.05). The newly developed CLDQ-HBV is a short, disease-specific PRO instrument for HBV patients which was developed and validated using large data set and an established methodology showing excellent psychometric characteristics.

Change in Viral Load Count and Its Predictors Among Unsuppressed Viral Load Patients Receiving an Enhanced Adherence Counseling Intervention at Three Hospitals in Northern Ethiopia: An Exploratory Retrospective Follow-Up Study.

BackgroundEnhanced adherence counseling (EAC) is an interventional program that provides targeted adherence counseling for unsuppressed viral load people living with HIV who are receiving antiretroviral therapy before diagnosing treatment failure. However, there is a lack of evidence on change in viral load count among patients receiving EAC intervention. Therefore, this study aimed to assess change in viral load count and its predictors among people living with HIV (PLHIV) in northeast Ethiopia.MethodsA hospital-based retrospective follow-up study was conducted on 235 randomly selected patients with unsuppressed viral load who started EAC sessions between 2016 and 2019 at three governmental hospitals in the northern part of Ethiopia. Viral load count and patient individual factors were assessed at EAC program enrollment and viral load counts repeated at the end of EAC session. The main outcome variable was a change in viral load count during the EAC session period. A paired sample t-test was used to determine the mean difference in viral load count before and after EAC intervention. Linear mixed-effects models were used to assess the effect of selected factors on viral load count change.ResultsBased on the paired sample t-test, there was a significant mean difference in viral load count before and after EAC intervention (mean difference=16,904, (95% CI: 9986–23,821; p-value<0.001). The multivariable linear mixed-effects regression analysis showed that young age (β= 0.03; 95% CI: 0.01, 0.14), urban residence (β= −0.55; 95% CI: −0.63, −0.34), CD4 count of 201–500 cells/mm3 (β= −0.67; 95% CI: −0.87, −0.43) and long duration on ART (β= −0.01; 95% CI: −0.01, −0.02) were associated with the decline in viral load count.ConclusionWe detected a substantial decline in viral load count among patients receiving an EAC intervention. Young age, urban residence, CD4 count of 201–500 cells/mm3 and long duration on ART were the positive predictors of viral load suppression.

Efficacy of Three Antiretroviral Regimens Initiated during Pregnancy: Clinical Experience in Rio de Janeiro.

Few studies have compared the clinical efficacy and adverse events of combined antiretroviral therapy (cART) regimens in pregnant women seeking obstetrical care. The objective of this study was to compare the efficacy (virus load response), adverse events, and obstetrical and neonatal outcomes of three different regimens of cART in HIV-infected pregnant women initiating treatment in Rio de Janeiro, Brazil. This was a retrospective cohort study of cART-naive pregnant women who initiated either ritonavir-boosted protease inhibitors (atazanavir or lopinavir), efavirenz, or raltegravir plus a backbone regimen. From 2014 to 2018, 390 pregnant women were followed over time. At baseline, the median viral load (VL) for HIV was 4.1 log copies/ml. Among participants who received cART for 2 to 7 weeks, the VL decline was greater for raltegravir (2.24 log copies/ml) than for efavirenz or protease inhibitors (P < 0.001). Virologic suppression was achieved in 87% of women on raltegravir near delivery versus 73% on efavirenz and 70% on protease inhibitors (P = 0.011). Patients on raltegravir achieved virologic suppression faster than those on other regimens (P = 0.019). Overall, the HIV perinatal infection rate was 1.5%. This clinical study compared three potent and well-tolerated cART regimens and demonstrated that a higher proportion of participants on raltegravir achieved an undetectable HIV VL near delivery (P = 0.011) compared to the other arms. These findings suggest that raltegravir-containing regimens are optimal regimens for women with HIV initiating treatment late in pregnancy.

SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (Covid-19), which is most frequently mild yet can be severe and life-threatening. Virus-neutralizing monoclonal antibodies are predicted to reduce viral load, ameliorate symptoms, and prevent hospitalization.MethodsIn this ongoing phase 2 trial involving outpatients with recently diagnosed mild or moderate Covid-19, we randomly assigned 452 patients to receive a single intravenous infusion of neutralizing antibody LY-CoV555 in one of three doses (700 mg, 2800 mg, or 7000 mg) or placebo and evaluated the quantitative virologic end points and clinical outcomes. The primary outcome was the change from baseline in the viral load at day 11. The results of a preplanned interim analysis as of September 5, 2020, are reported here.ResultsAt the time of the interim analysis, the observed mean decrease from baseline in the log viral load for the entire population was −3.81, for an elimination of more than 99.97% of viral RNA. For patients who received the 2800-mg dose of LY-CoV555, the difference from placebo in the decrease from baseline was −0.53 (95% confidence interval [CI], −0.98 to −0.08; P=0.02), for a viral load that was lower by a factor of 3.4. Smaller differences from placebo in the change from baseline were observed among the patients who received the 700-mg dose (−0.20; 95% CI, −0.66 to 0.25; P=0.38) or the 7000-mg dose (0.09; 95% CI, −0.37 to 0.55; P=0.70). On days 2 to 6, the patients who received LY-CoV555 had a slightly lower severity of symptoms than those who received placebo. The percentage of patients who had a Covid-19–related hospitalization or visit to an emergency department was 1.6% in the LY-CoV555 group and 6.3% in the placebo group.ConclusionsIn this interim analysis of a phase 2 trial, one of three doses of neutralizing antibody LY-CoV555 appeared to accelerate the natural decline in viral load over time, whereas the other doses had not by day 11. (Funded by Eli Lilly; BLAZE-1 ClinicalTrials.gov number, NCT04427501.)