Virological Rebound Research Articles

Emerging SARS-CoV-2 Resistance After Antiviral Treatment.

Previous studies have identified mutations in SARS-CoV-2 strains that confer resistance to nirmatrelvir, yet how often this resistance arises and its association with posttreatment virologic rebound is not well understood. To examine the prevalence of emergent antiviral resistance after nirmatrelvir treatment and its association with virologic rebound. This cohort study enrolled outpatient adults with acute COVID-19 infection from May 2021 to October 2023. Participants were divided into those who received antiviral therapy and those who did not. The study was conducted at a multicenter health care system in Boston, Massachusetts. Treatment regimen, including none, nirmatrelvir, and remdesivir. The primary outcome was emergent SARS-CoV-2 antiviral resistance, defined as the detection of antiviral resistance mutations, which were not present at baseline, were previously associated with decreased antiviral efficacy, and emerged during or after completion of a participant's treatment. Next-generation sequencing was used to detect low frequency mutations down to 1% of the total viral population. Overall, 156 participants (114 female [73.1%]; median [IQR] age, 56 [38-69] years) were included. Compared with 63 untreated individuals, the 79 who received nirmatrelvir were older and more commonly immunosuppressed. After sequencing viral RNA from participants' anterior nasal swabs, nirmatrelvir resistance mutations were detected in 9 individuals who received nirmatrelvir (11.4%) compared with 2 of those who did not (3.2%) (P = .09). Among the individuals treated with nirmatrelvir, those who were immunosuppressed had the highest frequency of resistance emergence (5 of 22 [22.7%]), significantly greater than untreated individuals (2 of 63 [3.1%]) (P = .01). Similar rates of nirmatrelvir resistance were found in those who had virologic rebound (3 of 23 [13.0%]) vs those who did not (6 of 56 [10.7%]) (P = .86). Most of these mutations (10 of 11 [90.9%]) were detected at low frequencies (<20% of viral population) and reverted to the wild type at subsequent time points. Emerging remdesivir resistance mutations were only detected in immunosuppressed individuals (2 of 14 [14.3%]) but were similarly low frequency and transient. Global Initiative on Sharing All Influenza Data analysis showed no evidence of increased nirmatrelvir resistance in the United States after the authorization of nirmatrelvir. In this cohort study of 156 participants, treatment-emergent nirmatrelvir resistance mutations were commonly detected, especially in individuals who were immunosuppressed. However, these mutations were generally present at low frequencies and were transient in nature, suggesting a low risk for the spread of nirmatrelvir resistance in the community with the current variants and drug usage patterns.

Use of next-generation sequencing on HIV-1 DNA to assess archived resistance in highly treatment-experienced people with multidrug-resistant HIV under virological control: data from the PRESTIGIO Registry.

To clarify whether next-generation sequencing (NGS) can be useful for resistance assessment in virologically suppressed highly treatment-experienced (HTE) individuals with MDR HIV. Ninety-one participants from the PRESTIGIO Registry were included. NGS was performed on HIV-DNA at 1%, 5% and 20% cut-offs; major drug resistance mutations (DRMs) were evaluated and compared with those detected in historical plasma genotypic resistance testing (h-GRT). APOBEC editing was also characterized. Participants had a complex and long treatment history [median 23 (IQR 21-25) years of ART exposure) and had been virologically suppressed since a median of 3 (IQR 2-5) years. Among all major DRMs detected by HIV-DNA NGS and/or h-GRT, 30% were exclusively found through NGS. The highest detection rate of historical major DRMs was reached with NGS set at 1%, but unusual substitutions and extensive APOBEC hypermutations suggest technical issues and poor clinical relevance in the 1%-5% interval. At NGS set at 5%, 67.2% of historical major DRMs were detected. The number of major DRMs detected exclusively by DNA-NGS as minority variants (frequency 5%-20%) was significantly higher in individuals who later experienced virological rebound compared with those who maintained virological control [median 2 (IQR 1-3) versus 1 (0-2), P = 0.030] and positively correlated with viraemia levels at rebound (rho = 0.474, P = 0.030). In non-viraemic people with an MDR virus, HIV-1 DNA NGS set at 5% is an acceptable technical cut-off that might help to reveal mutations with a potential clinical relevance. Moreover, the number of minority resistance mutations additionally detected by NGS might be associated with loss of virological control.

Association between markers of hepatitis B virus infection and risk of virological rebound in people with HIV receiving antiretroviral therapy.

The aim of this analysis was to investigate the impact of hepatitis B virus (HBV) coinfection on the risk of HIV viral rebound (VR) after achieving suppression for the first time following initiation of antiretroviral therapy (ART) in the real-world setting. Patients living with HIV (PLWH) who were enrolled in the ICONA Foundation Study cohort and achieved viral suppression ≤50 copies/mL for the first time after starting ART were prospectively evaluated and divided in three exposure groups according to serology test results: (a) HIV-monoinfected; (b) HIV-positive/HBcAb-positive/HBsAg-negative; (c) HIV-positive/HBsAg-positive. The occurrence of VR, defined as two consecutive HIV-RNA values >50 copies/mL after achieving viral suppression for the first time (baseline), was investigated. Standard survival analysis by means of Kaplan-Meier curves and Cox regression analysis with the serology exposure fitted as a time-fixed covariate measured at baseline was employed after controlling for key confounding factors. Of a total of 5657 patients included, 4090 (72%) were HIV-monoinfected, 1342 (23.7%)were HBcAb-positive, and 225 (3.9%) were HbsAg-positive coinfected. Overall, 654 (11.5%) PLWH experienced VR > 50 copies/mL during follow-up. After controlling for all sources of measured confounding, coinfected PLWH showed an increased risk of experiencing VR compared with those who were HIV-monoinfected. In particular, the strongest associations were seen for the HIV/HBsAg-positive participants [adjusted hazard ratio (aHR) = 1.56, 95% confidence interval (CI): 1.03-2.38, p = 0.037] but an excess of risk was also seen in those who were HIV-positive/HBcAb-positive/HBsAg-negative (aHR = 1.25, 95% CI: 1.00-1.55, p = 0.047). Coinfection with HBV seems to have an impact on the probability of maintaining HIV viral suppression achieved for the first time after ART initiation. Of note, even PLWH positive for HBcAb, a marker of inactive HBV infection, appeared to be at higher risk of VR compared with those who were HIV-monoinfected and their HIV-RNA should be carefully monitored.

SARS-CoV-2 infection rebound among patients receiving antiviral agents, convalescent plasma, or no treatment: a systematic review with meta-analysis.

There is some evidence showing rebound of COVID-19 infections in patients treated with nirmatrelvir-ritonavir between 2 and 8 days following cessation of the antiviral treatment. COVID-19 rebound is not unique to patients treated with nirmatrelvir-ritonavir, but is also observed in molnupiravir recipients, in patients who did not receive any antiviral treatment and in patients who received convalescent plasma (CP). This was a systematic review with meta-analysis of clinical trials evaluating rates of virologic and clinical rebound in COVID-19 patients receiving antiviral agents, CP or no treatment. Both randomized clinical trials and controlled cohort studies were considered. The methodological quality of trials was assessed using ROB-2 and ROBIN-1 checklists, and the GRADE approach. Data were available from 16 trials. The occurrence of virologic rebound was more commonly observed among nirmatrelvir recipients than among untreated patients (relative risk [RR]=2.12; 95% confidence interval [CI]: 1.38-3.28; p=0.0007). No differences were observed in the occurrence of virologic rebound between nirmatrelvir-ritonavir and molnupiravir recipients (RR=1.01; 95% CI: 0.71-1.43). Similar rates of virologic rebounds were observed in molnupiravir recipients and untreated patients (RR=1.14; 95% CI: 0.81-1.6). One study in the pre-omicron period compared rates of virologic rebound between patients receiving standard of care with or without CP: no differences were observed between groups (RR=1.04; 95% CI: 0.55-1.99). Rates of clinical rebound were reported in seven trials, five evaluating nirmatrelvir-ritonavir and untreated patients, and two evaluating nirmatrelvir-ritonavir and molnupiravir recipients. No statistically significant differences between groups were observed. For all these comparisons, the certainty of the available evidence was graded as low or moderate. Virologic rebound of COVID-19 infections appears to be mild and self-limited, and was observed more commonly in nirmatrelvir-ritonavir recipients than in untreated patients, but was also observed in patients treated with molnupiravir or CP.

Relationship Between Tenofovir Diphosphate Concentrations in Dried Blood Spots and Virological Outcomes After Initiating Tenofovir-Lamivudine-Dolutegravir as First-Line or Second-Line Antiretroviral Therapy.

Tenofovir diphosphate (TFV-DP) concentration in dried blood spots is a marker of long-term adherence. We investigated the relationship between TFV-DP concentrations and virological outcomes in participants initiating tenofovir-lamivudine-dolutegravir (TLD) as first-line or second-line antiretroviral therapy. Three primary care clinics in Khayelitsha, Cape Town, South Africa. We conducted a post hoc analysis of 2 randomized controlled trials of participants initiating TLD. TFV-DP concentrations and viral loads were measured at 12, 24, and 48 weeks. Multivariable logistic regression was performed to assess the association with virological suppression (<50 copies/mL) per natural logarithm increase in TFV-DP concentration. Generalized estimating equations with logit link were used to assess associations with virological rebound. The Akaike Information Criterion and Quasi-likelihood Information Criteria were used to compare models built on continuous TFV-DP data to 4 previously defined concentration categories. We included 294 participants in the analysis, 188 (64%) of whom initiated TLD as second-line therapy. Adjusted odds ratios (95% CIs) of virological suppression were 2.12 (1.23, 3.75), 3.11 (1.84, 5.65), and 4.69 (2.81, 8.68) per natural logarithm increase in TFV-DP concentration at weeks 12, 24, and 48, respectively. In participants with virological suppression at week 12, the adjusted odds ratio for remaining virologically suppressed was 3.63 (95% CI: 2.21 to 5.69) per natural logarithm increase in TFV-DP concentration. Models using continuous TFV-DP data had lower Akaike Information Criterion and Quasi-likelihood Information Criteria values than those using categorical data for predicting virological outcomes. TFV-DP concentrations in dried blood spots exhibit a dose-response relationship with viral load. Analyzing TFV-DP concentrations as continuous variables rather than conventional categorization may be appropriate.

Comparable clinical outcomes with same-day versus rapid initiation of antiretroviral therapy in Taiwan

ObjectivesWHO has recommended same-day antiretroviral therapy (SDART) initiation since 2017; however, higher attrition rates were noted in developing countries. MethodsWe included newly diagnosed people with HIV (PWH) from 2018 to 2022 at 18 hospitals around Taiwan. SDART initiation was defined as starting ART on the same day of HIV diagnosis and rapid initiation as starting ART within 14 days of diagnosis. A composite unfavorable outcome was defined as death after 30 days of diagnosis, loss to follow-up (LTFU), or virologic failure or rebound at 12 months. ResultsAt 12 months, PWH on SDART initiation and those on rapid ART initiation showed similar rates of engagement in care with plasma HIV-1 RNA <50 copies/mL (87.5% vs 87.7%) and composite unfavorable outcome (7.7% vs 7.7%). PWH aged >30 years were less likely to have LTFU (aHR 0.44, 95% CI 0.28-0.70). PWH aged >30 years (aHR 0.59, 95% CI 0.41-0.85) and gay, bisexual, and men who have sex with men (GBMSM) (aHR 0.50, 95% CI 0.32-0.79) were less likely to have composite unfavorable outcomes. ConclusionsSDART and rapid ART initiation resulted in comparable clinical outcomes and viral suppression rates. PWH aged >30 years and GBMSM were less likely to have unfavorable outcomes.

Intact proviruses are enriched in the colon and associated with PD-1+TIGIT− mucosal CD4+ T cells of people with HIV-1 on antiretroviral therapy

The persistence of intact replication-competent HIV-1 proviruses is responsible for the virological rebound off treatment. The gut could be a major reservoir of HIV-1 due to the high number of infected target cells. We collected blood samples and intestinal biopsies (duodenum, ileum, colon) from 42 people with HIV-1 receiving effective antiretroviral therapy. We used the Intact Proviral DNA Assay to estimate the frequency of intact HIV-1 proviruses in the blood and in the intestinal mucosa of these individuals. We analyzed the genetic complexity of the HIV-1 reservoir by performing single-molecule next-generation sequencing of HIV-1 env DNA. The activation/exhaustion profile of mucosal T lymphocytes was assessed by flow cytometry. Intact proviruses are particularly enriched in the colon. Residual HIV-1 transcription in the gut is associated with persistent mucosal and systemic immune activation. The HIV-1 intestinal reservoir appears to be shaped by the proliferation of provirus-hosting cells. The genetic complexity of the viral reservoir in the colon is positively associated with TIGIT expression but negatively with PD-1, and inversely related to its intact content. The size of the intact reservoir in the colon is associated with PD-1+TIGIT- mucosal CD4+ T cells, particularly in CD27+ memory cells, whose proliferation and survival could contribute to the enrichment of the viral reservoir by intact proviruses. Enrichment in intact proviruses makes the gut a key compartment for HIV-1 persistence on antiretroviral therapy. This project was supported by grants from the ANRS-MIE (ANRS EP61 GALT), Sidaction, and the Institut Universitaire de France.

Bictegravir/emtricitabine/tenofovir alafenamide in paediatrics: Real-life experience from a French cohort (2019-2023).

Although widely recommended, data on bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) efficacy in HIV-1-infected children/adolescents are mainly extrapolated from studies in adults and one paediatric trial in which subjects have good treatment adherence. This study aimed to provide data about the risk of virological failure (VF) and acquired genotypic resistance in children and adolescents receiving BIC/FTC/TAF in a real-world setting. This retrospective monocentric study included 74 paediatric patients who received BIC/FTC/TAF during ≥6 months in 2019-2023. VF was defined as not achieving a plasma viral load <50 copies/mL within 6 months of BIC/FTC/TAF initiation or as experiencing virological rebound ≥50 copies/mL. Most patients were antiretroviral therapy (ART)-experienced (93.2%), previously exposed to integrase inhibitors (85.1%) and displayed viral suppression at baseline (67.6%). Their median age was 11.2 years [interquartile range (IQR): 8.8-15.2]. BIC/FTC/TAF introduction reduced treatment burden in most ART-experienced subjects. Genotypic susceptibility score of BIC/FTC/TAF was ≥2 in all cases. Median follow-up was 40 months (IQR: 21-46). VF occurred in 28 people (37.8%), more frequently in the case of VF versus viral suppression at baseline (68% vs. 26%, P = 0.02). BIC/FTC/TAF was interrupted for suspected intolerance in only one case (1.4%). Nucleoside reverse transcriptase inhibitor (NRTI) mutation (T69D/N) emerged in one patient (3.6% of VF) after 47 months of continuous detectable viraemia while on ART. No acquisition of mutations in the integrase gene was observed. Because of its high genetic barrier to resistance, BIC/FTC/TAF could be especially useful in the paediatric population, in which the risk of poor treatment adherence and VF is high.

Long-acting Injectable Cabotegravir/Rilpivirine Effective in a Small Patient Cohort With Virologic Failure on Oral Antiretroviral Therapy.

We report 12 patients with persistent viremia on oral antiretroviral therapy who were initiated on injectable cabotegravir/rilpivirine (iCAB/RPV) without oral lead-in. All patients achieved viral suppression without any virologic rebound. iCAB/RPV may be considered as an option for patients unable to maintain suppression on oral antiretroviral therapy.

Safety Profile and Clinical and Virological Outcomes of Nirmatrelvir-Ritonavir Treatment in Patients With Advanced Chronic Kidney Disease and Coronavirus Disease 2019.

Nirmatrelvir-ritonavir is currently not recommended in patients with an estimated glomerular filtration rate (eGFR) <30 mL/minute/1.73 m2. To determine the safety profile and clinical and virological outcomes of nirmatrelvir-ritonavir use at a modified dosage in adults with chronic kidney disease (CKD), a prospective, single-arm, interventional trial recruited patients with eGFR <30 mL/minute/1.73 m2 and on dialysis. Primary outcomes included safety profile, adverse/serious adverse events, and events leading to drug discontinuation. Disease symptoms, virological outcomes by serial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral polymerase chain reaction (PCR) tests, rapid antigen tests, and virological and symptomatic rebound were also recorded. Fifty-nine (69.4%) of the 85 participants had stage 5 CKD and were on dialysis. Eighty (94.1%) completed the full treatment course; 9.4% and 5.9% had adverse and serious adverse events, and these were comparable between those with eGFR < or >30 mL/minute/1.73 m2. The viral load significantly decreased on days 5, 15, and 30 (P < .001 for all), and the reduction was consistent in the subgroup with eGFR <30 mL/minute/1.73 m2. Ten patients had virological rebound, which was transient and asymptomatic. Among patients with CKD, a modified dose of nirmatrelvir-ritonavir is a well-tolerated therapy in mild COVID-19 as it can effectively suppress the SARS-CoV-2 viral load with a favorable safety profile. Virological and symptomatic rebound, although transient with low infectivity, may occur after treatment. Nirmatrelvir-ritonavir should be considered for use in patients with CKD, including stage 5 CKD on dialysis. Clinical Trials Registration. Clinical Trials.gov; identifier: NCT05624840.

In vivo anti-hepatitis B activity of Artemisia argyi essential oil-loaded nanostructured lipid carriers. Study of its mechanism of action by network pharmacology and molecular docking

BackgroundHepatitis B virus (HBV) infection remains a major global health burden, due to the increasing risk of complications, such as cirrhosis and hepatocellular carcinoma. Novel anti-HBV agents are critical required. Our previous study suggested that Artemisia argyi essential oil (AAEO) significantly inhibited the replication of HBV DNA and especially the secretion of hepatitis B antigen in vitro. PurposeThe aim of this study was to prepare AAEO loaded nanostructured lipid carriers (AAEO-NLCs) for the delivery of AAEO to the liver, investigated the therapeutic benefits of AAEO-NLCs against HBV in a duck HBV (DHBV) model and explored its potential mechanism. Study design and methodsAAEO-NLCs were prepared by hot homogenization and ultrasonication method. The DHBV-infected ducks were treated with AAEO (4 mg/kg), AAEO-NLCs (0.8, 4, and 20 mg/kg of AAEO), and lamivudine (20 mg/kg) for 15 days. The DHBV DNA levels in the serum and liver were measured by quantitative Real-Time PCR. Pharmacokinetics and liver distribution were performed in rats after oral administration of AAEO-NLCs and AAEO suspension. The potential antiviral mechanism and active compounds of AAEO were investigated by network pharmacology and molecular docking. ResultsAAEO-NLCs markedly inhibited the replication of DHBV DNA in a dose-dependent manner and displayed a low virologic rebound following withdrawal the treatment in DHBV-infected ducks. Moreover, AAEO-NLCs led to a more pronounced reduction in viral DNA levels than AAEO suspension. Further investigations of pharmacokinetics and liver distribution in rats confirmed that NLCs improved the oral bioavailability and increased the liver exposure of AAEO. The potential mechanisms of AAEO against HBV explored by network pharmacology were associated with signaling pathways related to immune response, such as tumor necrosis factor, nuclear factor kappa B, and sphingolipid signaling pathways. Furthermore, a total of 16 potential targets were obtained, including prostaglandin-endoperoxide synthase-2 (PTGS2), caspase-3, progesterone receptor, etc. Compound-target docking results confirmed that four active compounds of AAEO had strong binding interactions with the active sites of PTGS2. ConclusionsAAEO-NLCs displayed potent anti-HBV activity with improved oral bioavailability and liver exposure of AAEO. Thus, it may be a potential therapeutic strategy for the treatment of HBV infection.

Nirmatrelvir-ritonavir therapy and COVID-19 vaccination improve clinical outcomes of SARS-CoV-2 Omicron variant infection.

To evaluate the effect of Nirmatrelvir-ritonavir therapy and coronavirus disease 2019(COVID-19) vaccination on clinical outcomes of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) Omicron infection, we retrospectively analyzed the clinical data of 762 adult patients with confirmed Omicron BA2.2 variant infection, of them 488 patients received standard therapy and 274 patients received Nirmatrelvir-ritonavir therapy. Subjects were matched by propensity score matching using R language, the baseline factors were balanced by the nearest-neighbor matching method and were compared, together with the factors including progression to severe/critical disease, viral clearance time, length of hospital stay, and virological rebound of SARS-CoV-2 infection. Nirmatrelvir-ritonavir therapy significantly accelerated viral clearance at Days 14 and 28 during hospitalization, but it had no impact on disease progression, length of hospital stay, or infection rebound. In contrast, COVID-19 vaccination before admission was positively correlated with the viral clearance rate and negatively correlated with disease progression in a dose-dependent way. COVID-19 vaccination reduced the probability of infection rebound. Other factors such as the number of comorbidities, pneumonia on-admission, and high D2 levels were positively correlated with disease progression. Our study strongly recommended booster COVID-19 vaccination for the elderly population, particularly patients with comorbidities to prevent critical disease.

Coronavirus disease 2019 rebounds following nirmatrelvir/ritonavir treatment.

Nirmatrelvir/ritonavir (NMV-r) is an effective anti-SARS-CoV-2 agent and has been recommended in the treatment of non-hospitalized patients with COVID-19. In rare occasions, some patients experience virologic and symptomatic rebound after initial resolution, which we call COVID-19 rebound after NMV-r. Although COVID rebound can also occur after molnupiravir treatment or even no antiviral treatment, we have more serious concern about the rebound after NMV-r, which remains the most effective antiviral. Due to a lack of information about its frequency, mechanism, outcomes, and management, we conducted this review to provide comprehensive and updated information to address these questions. Based on the limited evidence, the incidence of COVID-19 rebound after NMV-r was less than 2%, and most cases developed 5-15 days after initiating NMV-r treatment. Almost all reported cases had mild symptoms, and the clinical condition gradually subsided without additional treatment. Overall, the clinical outcome was favourable, and only a small number of patients required emergency department visits or hospitalization. Regarding virologic rebound, culturable SARS-CoV-2 with possible transmission was observed, so re-isolation may be needed. This article is protected by copyright. All rights reserved.

Efficacy of ultra-short, response-guided sofosbuvir and daclatasvir therapy for hepatitis C in a single-arm mechanistic pilot study.

World Health Organization has called for research into predictive factors for selecting persons who could be successfully treated with shorter durations of direct-acting antiviral (DAA) therapy for hepatitis C. We evaluated early virological response as a means of shortening treatment and explored host, viral and pharmacokinetic contributors to treatment outcome. Duration of sofosbuvir and daclatasvir (SOF/DCV) was determined according to day 2 (D2) virologic response for HCV genotype (gt) 1- or 6-infected adults in Vietnam with mild liver disease. Participants received 4- or 8-week treatment according to whether D2 HCV RNA was above or below 500 IU/ml (standard duration is 12 weeks). Primary endpoint was sustained virological response (SVR12). Those failing therapy were retreated with 12 weeks SOF/DCV. Host IFNL4 genotype and viral sequencing was performed at baseline, with repeat viral sequencing if virological rebound was observed. Levels of SOF, its inactive metabolite GS-331007 and DCV were measured on days 0 and 28. Of 52 adults enrolled, 34 received 4 weeks SOF/DCV, 17 got 8 weeks and 1 withdrew. SVR12 was achieved in 21/34 (62%) treated for 4 weeks, and 17/17 (100%) treated for 8 weeks. Overall, 38/51 (75%) were cured with first-line treatment (mean duration 37 days). Despite a high prevalence of putative NS5A-inhibitor resistance-associated substitutions (RASs), all first-line treatment failures cured after retreatment (13/13). We found no evidence treatment failure was associated with host IFNL4 genotype, viral subtype, baseline RAS, SOF or DCV levels. Shortened SOF/DCV therapy, with retreatment if needed, reduces DAA use in patients with mild liver disease, while maintaining high cure rates. D2 virologic response alone does not adequately predict SVR12 with 4-week treatment. Funded by the Medical Research Council (Grant MR/P025064/1) and The Global Challenges Research 70 Fund (Wellcome Trust Grant 206/296/Z/17/Z).

304. Viral resistance analysis in the COMET-PEAK study: sotrovimab treatment in participants with mild-to-moderate COVID-19

Abstract Background Sotrovimab is a human monoclonal antibody targeting a conserved region of the SARS-CoV-2 spike (S) protein. COMET-PEAK was a 3-part, phase 2 study that evaluated intravenous (500 mg) and intramuscular (500 mg and 250 mg) administration of sotrovimab in outpatients (n=353) with mild-to-moderate COVID-19. We assessed amino acid substitutions in the SARS-CoV-2 S protein and circulating variants of concern/interest (VOC/VOI) in COMET-PEAK participants (enrolled Feb–July 2021). Methods Mid-turbinate (Part A) or nasopharyngeal (Part B/C) samples were obtained from all participants at Baseline and Post-Baseline visits. Next generation sequencing of the SARS-CoV-2 S gene was conducted using Illumina MiSeq with a ≥5% allelic frequency cut-off for samples with a viral load above 3.0 log10 copies/mL. Baseline, post-baseline and treatment-emergent (TE) substitutions were assessed, and prevalence of VOC/VOI was evaluated. Phenotypic analyses of epitope substitutions were conducted using a pseudotyped virus assay. Results In total, 282/353 participants had sequencing results for ≥1 visit (253 baseline, 248 post-baseline), and 219 had paired baseline and post-baseline sequences; among these, 149 (68%) had TE substitutions in the S protein (26 [12%] in the epitope). E340K was the predominant TE substitution in the epitope (15 [7%]). Across all arms 92/245 (38%) experienced virologic rebound, 8 of whom (Part A: 2; Part B: 2; Part C: 4) had TE substitutions in the epitope; none had evidence of clinical progression to severe disease. Prevalence of VOC/VOI or single amino acid substitutions of concern was 94% (266/282); the most frequent were Alpha (Part A: 8/16 [50%]; Part B: 75/128 [59%]) and Delta (Part C: 99/122 [81%]). Of 7 participants with evidence of clinical progression, none had S protein substitutions in the epitope and all had VOC/VOI (3 Alpha, 3 Delta, 1 Gamma). Sotrovimab effectively neutralized most epitope substitutions tested in vitro; P337L and E340A/K/V conferred significantly reduced susceptibility. Conclusion There was no evidence that sotrovimab epitope substitutions were associated with clinical progression or virologic rebound. These data are consistent with those from the COMET-ICE study. Funding Vir Biotechnology/GSK (NCT04779879). Disclosures Phillip J Yates, PhD, GlaxoSmithKline: Employee Jennifer Moore, MD, GlaxoSmithKline: Employee Jennifer Han, MD, GlaxoSmithKline: Employee Andrew Skingsley, MD, GlaxoSmithKline: Employee|GlaxoSmithKline: Stocks/Bonds Gretja Schnell, PhD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Andrea L. Cathcart, PhD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Melissa Aldinger, PharmD, Vir Biotechnology: Employee|Vir Biotechnology: Stocks/Bonds Amanda Peppercorn, MD, GlaxoSmithKline: Employee|GlaxoSmithKline: Stocks/Bonds Jill Walker, PhD, GlaxoSmithKline: Employee.

1279. Real World Treatment Experience of Treatment-Naïve People with HIV who Initiated Treatment with Single Tablet Dolutegravir/Lamivudine in a Test and Treat setting in the US.

Abstract Background Dolutegravir/lamivudine (DTG/3TC) is indicated as a 2DR for both treatment-naïve and virally suppressed PLWH. The feasibility of DTG/3TC use in a Test &amp; Treat (T&amp;T) setting has been demonstrated in a clinical trial, but there is limited evidence with this approach in US real world clinical settings. Methods TANDEM was a retrospective medical chart review conducted across 24 US sites. Eligible PLWH were adults initiated on DTG/3TC or DTG/rilpivirine (DTG/RPV) prior to Sept/30/2020 with a minimum clinical follow-up of six months. Treatment-naïve (TN) PLWH had no prior history of HIV therapy. Clinical characteristics, treatment history and outcomes were abstracted. Analyses were descriptive. Reported here are results for the sub-group of TN PLWH that were initiated DTG/3TC as part of a T&amp;T strategy, defined as clinician attestation of treatment initiation shortly after diagnosis and in the absence of known lab values for HIV-1 RNA viral load, CD4 cell count and HIV-1 resistance mutations. Results From an overall sample of 469 PLWH on DTG-based 2DR, 318 received DTG/3TC, of whom, 126 were TN and 192 were stable switch. Almost half 48% of PLWH received DTG/3TC as part of a T&amp;T paradigm. Characteristics of the cohort are described in Table 1. In the T&amp;T sub-group, the most common reasons for initiating DTG/3TC were avoidance of long-term toxicities (n=26), followed by simplification/streamlining (n=8) and convenience (n=7). Overall, 114 (90.5%) of TN PLWH achieved the desired health outcome per clinician attestation. At data cut-off, 61 (94%) non T&amp;T achieved virologic suppression, 57 (93%) of the T&amp;T sub-group achieved virological suppression, 3 (5%) did not, and 1 (2%) was still unknown. Of the 3 who did not achieve suppression, 2 remained on DTG/3TC while 1 was switched to bictegravir/emtricitabine/tenofovir alafenamide. Virologic rebound occurred in 6 TN PLWH overall with only 1 occurring in the T&amp;T sub-group. Baseline Characteristics and Virologic Outcomes Conclusion Reflecting results from clinical trials, DTG/3TC achieved its desired health outcomes in the majority of cases regardless of treatment paradigm, with virtually no difference in virological suppression rates across the two cohorts (93-94% achieving suppression in a median duration of 10-11 weeks). Disclosures Cindy Donovan, PharmD, Johnson &amp; Johnson: Stocks/Bonds|ViiV Healthcare: Employee/Salary|ViiV Healthcare: Stocks/Bonds Gavin Harper, BA, ViiV Healthcare: Adelphi Real World were paid consultants (CRO) to conduct the observational research study on behalf of ViiV Healthcare.|ViiV Healthcare: Adelphi Real World were paid consultants (CRO) to conduct the observational research study on behalf of ViiV Healthcare Deanna Merrill, PharmD, MBA, AAHIVP, ViiV Healthcare: Salaried employee|ViiV Healthcare: Stocks/Bonds Katie L. Mycock, MChem, ViiV Healthcare: Adelphi Real World were paid consultants (CRO) to conduct the observational research study on behalf of ViiV Healthcare|ViiV Healthcare: Adelphi Real World were paid consultants (CRO) to conduct the observational research study on behalf of ViiV Healthcare Alan Oglesby, MPH, GlaxoSmithKline (GSK): Employment|GlaxoSmithKline (GSK): Stocks/Bonds Aimee Metzner, PharmD, AAHIVP, ViiV Healthcare: Salaried employee|ViiV Healthcare: Stocks/Bonds Jimena Patarroyo, PharmD, AAHIVP, ViiV Healthcare: Salaried employee|ViiV Healthcare: Stocks/Bonds|ViiV Healthcare: Stocks/Bonds.

1278. Real World Treatment Experience of Single Tablet Dolutegravir/Lamivudine in Those Naïve to Treatment with Baseline Viral Loads ≥ 100,000 copies/mL in the US

Abstract Background Treatment for people living with HIV-1 (PLWH) continues to advance with a two-drug regimen (2DR) approach. Dolutegravir/lamivudine (DTG/3TC) is indicated as a 2DR for both treatment-naïve and virally suppressed PLWH. Despite high and sustained virologic efficacy for DTG-based 2DRs observed in clinical trials, there is limited evidence in US real world clinical settings. This study characterizes prescribing behaviors and treatment outcomes for DTG-based 2DR in the real world. Methods TANDEM was a retrospective medical chart review conducted across 24 US sites. Eligible PLWH were adults initiated on single tablet DTG/3TC or DTG/rilpivirine prior to Sept/30/2020 with a minimum clinical follow-up of six months. Treatment-naïve PLWH had no prior history of HIV therapy. Clinical characteristics, treatment history and outcomes were abstracted. Analyses were descriptive. Reported here are viral outcomes for the DTG/3TC cohort of treatment-naïve PLWH with baseline viral loads (VLs) ≥ 100,000 (c/mL). Results From an overall sample of 469 PLWH on DTG-based 2DR, 318 received DTG/3TC. Of the DTG/3TC cohort, 126 were treatment-naïve. Of the treatment-naïve, 58 PLWH had known VLs available at DTG/3TC initiation. For those with baseline VLs ≥ 100,000 c/mL, 9 had values 100,000-250,000 c/mL while 7 were &amp;gt; 250,000 c/mL. Characteristics of this sub-cohort are described in Table 1. Overall, the most common reason for DTG/3TC initiation in this sub-cohort was patient preference (n=5), followed by avoidance of long-term toxicities and convenience (both n=3). For those with VLs between 100-250k, median CD4 count was 312 while 8/9 became virally suppressed (HIV-1 RNA &amp;lt; 50c/mL) and 1 PLWH had missing data. For those with VLs &amp;gt; 250k, median CD4 count was 114 while 6/7 became virally suppressed and 1 PLWH had missing data. One of these 6 PLWH experienced virologic rebound yet remained on DTG/3TC. Table 1:Clinical Characteristics Conclusion These real world results reflect data from clinical trials, demonstrating DTG/3TC is effective and well tolerated in the real world. Nearly all DTG/3TC users, regardless of baseline VL, experienced sustained virologic suppression with few treatment discontinuations. Caution should be used when extrapolating these results due to limited population size of the sub-cohorts. Disclosures Paul Benson, DO, AAHIVS, ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Speakers Bureau and Advisory Boards Cindy Donovan, PharmD, Johnson &amp; Johnson: Stocks/Bonds|ViiV Healthcare: Employee/Salary|ViiV Healthcare: Stocks/Bonds Gavin Harper, BA, ViiV Healthcare: Adelphi Real World were paid consultants (CRO) to conduct the observational research study on behalf of ViiV Healthcare.|ViiV Healthcare: Adelphi Real World were paid consultants (CRO) to conduct the observational research study on behalf of ViiV Healthcare Deanna Merrill, PharmD, MBA, AAHIVP, ViiV Healthcare: Salaried employee|ViiV Healthcare: Stocks/Bonds Katie L. Mycock, MChem, ViiV Healthcare: Adelphi Real World were paid consultants (CRO) to conduct the observational research study on behalf of ViiV Healthcare|ViiV Healthcare: Adelphi Real World were paid consultants (CRO) to conduct the observational research study on behalf of ViiV Healthcare Alan Oglesby, MPH, GlaxoSmithKline (GSK): Employment|GlaxoSmithKline (GSK): Stocks/Bonds Jimena Patarroyo, PharmD, AAHIVP, ViiV Healthcare: Salaried employee|ViiV Healthcare: Stocks/Bonds|ViiV Healthcare: Stocks/Bonds Aimee Metzner, PharmD, AAHIVP, ViiV Healthcare: Salaried employee|ViiV Healthcare: Stocks/Bonds.

Evaluation of antiretroviral therapy effect and prognosis between HIV-1 recent and long-term infection based on a rapid recent infection testing algorithm.

Early diagnosis of HIV-1 infection and immediate initiation of combination antiretroviral therapy (cART) are important for achieving better virological suppression and quicker immune reconstitution. However, no serological HIV-1 recency testing assay has been approved for clinical use, and the real-world clinical outcomes remain to be explored for the subjects with HIV-1 recent infection (RI) or long-term infection (LI) when antiretroviral therapy is initiated. In this study, a HIV-1 rapid recent-infection testing strip (RRITS) was developed and incorporated into the recent infection testing algorithms (RITAs) to distinguish HIV-1 RI and LI and to assess their clinical outcomes including virological response, the recovery of CD4+ T-cell count and CD4/CD8 ratio and the probability of survival. We found that the concordance between our RRITS and the commercially available LAg-Avidity EIA was 97.13% and 90.63% when detecting the longitudinal and cross-sectional HIV-1 positive samples, respectively. Among the 200 HIV-1 patients analyzed, 22.5% (45/200) of them were RI patients and 77.5% (155/200) were chronically infected and 30% (60/200) of them were AIDS patients. After cART, 4.1% (5/155) of the LI patients showed virological rebound, but none in the RI group. The proportion of CD4+ T-cell count >500 cells/mm3 was significantly higher in RI patients than in LI after 2 years of cART with a hazard ratio (HR) of 2.6 (95% CI: 1.9, 3.6, p < 0.0001) while the probability of CD4/CD8 = 1 was higher in RI than in LI group with a HR of 3.6 (95% CI: 2.2, 5.7, p < 0.0001). Furthermore, the immunological recovery speed was 16 cells/mm3/month for CD4+ T-cell and 0.043/month for the ratio of CD4/CD8 in the RI group, and was bigger in the RI group than in the LI patients (p < 0.05) during the 1st year of cART. The survival probability for LI patients was significantly lower than that for RI patients (p < 0.001). Our results indicated that RRITS combined with RITAs could successfully distinguish HIV-1 RI and LI patients whose clinical outcomes were significantly different after cART. The rapid HIV-1 recency test provides a feasible assay for diagnosing HIV-1 recent infection and a useful tool for predicting the outcomes of HIV-1 patients.

Real world efficacy of dolutegravir plus lamivudine in people living with HIV with undetectable viral load after previous failures

Dolutegravir (DTG) +lamivudine (3TC) combination has been found to be as effective as triple therapies, and has been extensively prescribed in clinical practice as a maintenance therapy. We aimed to investigate the effect of previous virological failures (VFs) on virological efficacy. The analysis included data of people living with HIV (PLWH) with HIV-RNA ≤50 copies/mL enrolled in an Italian retrospective multicohort study who were switching to DTG+3TC. Primary endpoint was viral rebound (VR; confirmed HIV-RNA ≥50 copies/mL or single HIV-RNA ≥50 copies/mL followed by change of antiretroviral therapies [ART]). Kaplan-Meier curves were used to estimate probabilities of VR based upon histories of previous VFs (single HIV-RNA ≥1000 copies/mL or confirmed HIV-RNA ≥50 copies/mL). A weighted Cox regression model was fitted to estimate the causal hazard ratio (HR) of history of failure on the risk of VR. A total of 966 PLWH were included; 20.1% had a history of previous VF. VR was detected in 23 PLWH. The one-year probability was 1.2% (95% confidence interval [CI], 0.2%-2.2%) in PLWH without previous VF and 3.3% (95% CI, 0.4%-6.2%) in those with ≥1 VF (log-rank P = 0.042). By multivariate analysis adjusted for CD4+ cell count at nadir, duration of virological suppression, and mode of HIV transmission, PLWH with ≥1 previous VF had a higher risk of virological rebound than those without previous VF (adjusted hazard ratio 3.06 [95% CI, 1.00-9.44], P = 0.051). Despite the low absolute one-year risk in both groups, real-world data confirmed that PLWH with a previous failure have an increased risk of viral rebound.

Virological efficacy of switch to DTG plus 3TC in a retrospective observational cohort of suppressed HIV-1 patients with or without past M184V: the LAMRES study

The aim of this study was to assess the efficacy of dolutegravir plus lamivudine (DTG+3TC) in a large set of virologically suppressed HIV-1 infected individuals with or without past M184V mutation. This observational study included individuals who switched to DTG+3TC with ≥1 genotype before switch. Survival analysis was used to evaluate the role of past M184V on virological rebound (VR) or blips after DTG+3TC switch. A total of 712 individuals followed in several clinical centres in France, Italy and Spain were analysed. Past M184V was present in 60 (8.4%) individuals. By 3 years after switch, the overall probability of VR and blips was 6.7% and 6.9%, respectively, without any statistical significance according to the presence/absence of past M184V. A significantly higher probability of VR was found in individuals harbouring M184V before DTG+3TC with a duration of virological suppression (Ts) ≤.3.5 years compared to others (M184V+Ts ≤.3.5 years: 22.7%; M184M+Ts ≤.3.5 years: 9.0%; M184V+Ts >3.5 years: 7.8%; M184M+Ts >3.5 years: 4.9%; P=0.007). This finding was not confirmed in multivariable models adjusting for behavioural and demographic variables. Genotypic resistance test after VR under DTG+3TC was available for 8/39 individuals; one poorly adherent individual developed M184V. No resistance to INIs was found. In this retrospective observational study, the probability of VR and blips in patients switching to DTG+3TC was very low after 3 years of treatment regardless M184V. The effect of a short duration of previous virological suppression in individuals with M184V remains troubling and needs ad hoc clinical trials to be confirmed.