Viral Load Rebound Research Articles

Comparative Emergence of Maribavir and Ganciclovir Resistance in a Randomized Phase 3 Clinical Trial for Treatment of Cytomegalovirus Infection

Abstract Background Among 547 patients receiving maribavir or valganciclovir for first-episode cytomegalovirus infection after hematopoietic cell transplant, the treatment response rate was 69.6% and 77.4% respectively. Development of maribavir and ganciclovir resistance was compared after receiving either drug. Methods Viral mutations conferring drug resistance were analyzed in plasma DNA extracts at baseline and post-treatment. Results Prior antiviral drug exposure was limited, with only 2 instances of baseline drug resistance detected. An equal number (n=241) received valganciclovir or maribavir for at least 21 days (median 55-56 days). Among them, drug resistance mutations were detected in 24 (10%) maribavir recipients at 35-125 days (median 56) after starting therapy, including in 12 of 14 who experienced a viral load rebound while on therapy. Ganciclovir resistance mutations developed in 6 (2.5%) valganciclovir recipients at 66-110 days (median 90). One maribavir recipient developed a novel UL97 gene mutation (P-loop substitution G343A) that conferred strong maribavir and ganciclovir resistance in vitro. Viral clearance was confirmed in 17 (74%) of 23 patients with emergent maribavir resistance after re-treatment with an alternative CMV antiviral drug. Conclusion After 3-8 weeks of therapy, maribavir resistance emerged earlier and more frequently than ganciclovir resistance but was usually treatable using alternative therapy. Clinical Trials Registration NCT02927067 (AURORA)

Mosaic vaccine-induced antibody-dependent cellular phagocytosis associated with delayed HIV-1 viral load rebound post treatment interruption

A heterologous Ad26/MVA vaccine was given prior to an analytic treatment interruption (ATI) in people living with HIV-1 (mainly CRF01_AE) who initiated antiretroviral treatment (ART) during acute HIV-1. We investigate the impact of Ad26/MVA vaccination on antibody (Ab)-mediated immune responses and their effect on time to viral rebound. The vaccine mainly triggers vaccine-matched binding Abs while, upon viral rebound post ATI, infection-specific CRF01_AE binding Abs increase in all participants. Binding Abs are not associated with time to viral rebound. The Ad26/MVA mosaic vaccine profile consists of correlated non-CRF01_AE binding Ab and Fc effector features, with strong Ab-dependent cellular phagocytosis (ADCP) responses. CRF01_AE-specific ADCP responses (measured either prior to or post ATI) are significantly higher in individuals with delayed viral rebound. Our results suggest that vaccines eliciting cross-reactive responses with circulating viruses in a target population could be beneficial and that ADCP responses may play a role in viral control post treatment interruption.

Real-world effectiveness of molnupiravir, azvudine and paxlovid against mortality and viral clearance among hospitalized patients with COVID-19 infection during the omicron wave in China: A retrospective cohort study

ObjectivesIn this retrospective cohort study, we aimed to assess clinical effectiveness and viral clearance following the use of molnupiravir, azvudine and paxlovid in hospitalized patients with COVID-19 in China dominated by the omicron BA.5.2 and BF.7 subvariant of SARS-CoV-2. MethodsEnrolled patients were assigned to the molnupiravir group or the azvudine group or the paxlovid group or the control group (not taking any antiviral drugs). The primary outcome of the cohort study was viral clearance and viral burden rebound after treatment and the secondary outcome was 28-day all-cause mortality. The four groups were propensity score-matched (1:1). We plotted viral load trends for each antiviral drug intervention using locally weighted regression (LOWESS) smoothed data. Multivariate logistic regression (stepwise algorithm) models were used to determine any risk factors for 28-day mortality. ResultsOf the 1537 patients receiving any treatment, 886 (57.6 %) received molnupiravir, 390 (25.4 %) received azvudine, 94 (6.1 %) received paxlovid, and 167 (10.9 %) did not use any antiviral drugs. Our data analysis showed that age (OR = 1.05, 95 % CI: 1.03-1.07, P < 0.001), Charlson comorbidty index (OR = 1.32, 95 % CI: 1.18-1.48, P < 0.001), severity of COVID-19 (P < 0.001), gamma globulin (OR = 2.04, 95 % CI: 1.03-3.99, P = 0.039) and corticosteroids use (OR = 2.3, 95 % CI: 1.19-4.69, P = 0.017) were independent prognostic factors for 28-day mortality in COVID-19 patients. After propensity score matching (PSM), the paxlovid recipients (OR = 0.22, 95 % CI: 0.05–0.83, P = 0.036) or azvudine recipients (OR = 0.27, 95 % CI: 0.07-0.91, P = 0.046) had lower 28-day mortality compared to their matched controls. Viral rebound occurred in the control group around days 9-16, while no viral rebound was found in any of the three oral antiviral groups. We found that molnupiravir group performed comparably in terms of the rate of nucleic acid conversion negative compared with the paxlovid group, while azvudine group performed slightly worse compared with the paxlovid group or molnupiravir group. ConclusionsIn our retrospective cohort of hospitalized patients with COVID-19 during the wave of omicron strain, the molnupiravir, paxlovid and azvudine recipients showed a faster and more stable decrease in viral load and rare virus rebound in response to antiviral treatments when compared to the controls. The study supported that initiation treatment with paxlovid and azvudine was associated with significantly lower risk of all-cause death within 28 days.

Changes in access to viral load testing, incidence rates of viral load suppression and rebound following the introduction of the 'universal test and treat' guidelines in Cameroon: A retrospective follow-up analysis.

Cameroon adopted and started implementing in 2016, the 'universal test and treat' (UTT) guidelines to fast-track progress towards the 95-95-95 ambitious targets to end the HIV epidemic. Achieving the third 95 (viral load suppression) is the most desirable target in HIV care. We aimed to evaluate the effectiveness of this novel approach on access to viral load testing (VLT), viral suppression (VLS), and viral load rebound (VLR). A retrospective cohort study was conducted at The Nkongsamba Regional Hospital to compare VLT outcomes between the pre-UTT (2002 to 2015) and the post-UTT (2016 to 2020) periods. We used a data extraction form to collect routine data on adult patients living with HIV. We measured uptake levels of the first and serial VLT and compared the incidence rates of VLS (VL<1000 copies/ml) and viral load rebound (VLR) before and after introducing the UTT approach using Kaplan Meier plots and log-rank tests. Cox regression was used to screen for factors independently associated with VLS and VLR events between the guideline periods. Access to initial VLT increased significantly from 6.11% to 25.56% at 6 months and from 12.00% to 73.75% at 12 months before and after introducing the UTT guidelines respectively. After a total observation time at risk of 17001.63 person-months, the UTT group achieved an incidence rate of 90.36 VLS per 1000 person-months, four-fold higher than the 21.71 VLS per 1000 person-months observed in the pre-UTT group (p<0.0001). After adjusting for confounding, the VLS rate was about 6-fold higher in the UTT group than in the pre-UTT group (adjusted Hazard Rate (aHR) = 5.81 (95% confidence interval (95%CI): 4.43-7.60). The incidence of VLR increased from 12.60 (95%CI: 9.50-16.72) to 19.11 (95%CI: 14.22-25.67) per 1000 person-months before and after the introduction of UTT guidelines respectively. After adjusting, VLR was more than twice as high in the UTT group than in the pre-UTT group (aHR = 2.32, 95%CI: 1.30-4.13). Increased access to initial VLT and higher rates of VLS have been observed but there are concerns that the suppressed viral load may not be durable since the introduction of the UTT policy in this setting.

COVID-19 Rebound After VV116 vs Nirmatrelvir-Ritonavir Treatment

With the widespread use of anti-SARS-CoV-2 drugs, accumulating data have revealed potential viral load rebound after treatment. To compare COVID-19 rebound after a standard 5-day course of antiviral treatment with VV116 vs nirmatrelvir-ritonavir. This is a single-center, investigator-blinded, randomized clinical trial conducted in Shanghai, China. Adult patients with mild-to-moderate COVID-19 and within 5 days of SARS-CoV-2 infection were enrolled between December 20, 2022, and January 19, 2023, and randomly allocated to receive either VV116 or nirmatrelvir-ritonavir. Participants in the VV116 treatment group received oral 600-mg VV116 tablets every 12 hours on day 1 and 300 mg every 12 hours on days 2 through 5. Participants in the nirmatrelvir-ritonavir treatment group received oral nirmatrelvir-ritonavir tablets with 300 mg of nirmatrelvir plus 100 mg of ritonavir every 12 hours for 5 days. Participants were followed up every other day until day 28 and every week until day 60. The primary outcome was viral load rebound (VLR), defined as a half-log increase in viral RNA copies per milliliter compared with treatment completion. Secondary outcomes included a reduction in the cycle threshold value of 1.5 or more, time until VLR, and symptom rebound, defined as an increase of more than 2 points in symptom score compared with treatment completion. The primary outcome and secondary outcomes were analyzed using the full analysis set. Sensitivity analyses were conducted using the per protocol set. Adverse events were analyzed using the safety analysis set. The full analysis set included 345 participants (mean [SD] age, 53.2 [16.8] years; 175 [50.7%] were men) who received VV116 (n = 165) or nirmatrelvir-ritonavir (n = 180). Viral load rebound occurred in 33 patients (20.0%) in the VV116 group and 39 patients (21.7%) in the nirmatrelvir-ritonavir group (P = .70). Symptom rebound occurred in 41 of 160 patients (25.6%) in the VV116 group and 40 of 163 patients (24.5%) in the nirmatrelvir-ritonavir group (P = .82). Viral whole-genome sequencing of 24 rebound cases revealed the same lineage at baseline and at viral load rebound in each case. In this randomized clinical trial of patients with mild-to-moderate COVID-19, viral load rebound and symptom rebound were both common after a standard 5-day course of treatment with either VV116 or nirmatrelvir-ritonavir. Prolongation of treatment duration might be investigated to reduce COVID-19 rebound. Chinese Clinical Trial Registry Identifier: ChiCTR2200066811.

Dynamic heterogeneity in COVID-19: Insights from a mathematical model.

Critical illness, such as severe COVID-19, is heterogenous in presentation and treatment response. However, it remains possible that clinical course may be influenced by dynamic and/or random events such that similar patients subject to similar injuries may yet follow different trajectories. We deployed a mechanistic mathematical model of COVID-19 to determine the range of possible clinical courses after SARS-CoV-2 infection, which may follow from specific changes in viral properties, immune properties, treatment modality and random external factors such as initial viral load. We find that treatment efficacy and baseline patient or viral features are not the sole determinant of outcome. We found patients with enhanced innate or adaptive immune responses can experience poor viral control, resolution of infection or non-infectious inflammatory injury depending on treatment efficacy and initial viral load. Hypoxemia may result from poor viral control or ongoing inflammation despite effective viral control. Adaptive immune responses may be inhibited by very early effective therapy, resulting in viral load rebound after cessation of therapy. Our model suggests individual disease course may be influenced by the interaction between external and patient-intrinsic factors. These data have implications for the reproducibility of clinical trial cohorts and timing of optimal treatment.

Factors associated with viral suppression and rebound in children and adolescents living with HIV on antiretroviral treatment at the Bangui pediatric complex, Central African Republic

Background: Suppression of viral load and its maintenance is the necessary condition for reducing mortality linked to HIV infection in children. This study aimed to investigate the factors associated with viral load rebound in children receiving antiretroviral treatment. Methods: This was a cross-sectional study with analytical purposes, running from August 1 to 31, 2023. Were inclusive, all children living with HIV under 15 years of age, with at least two viral load results and whose parents have agreed to participate in the study. Results: A total of 286 children were included in the study. The mean age was 11.5 years (±2.8). More than half (55.2%) of the children were not informed of their HIV status and for the majority (50.3%). Among the 198 children with a suppressed viral load at the first test, 46 (23.2%) experienced a rebound in viral load at the last test. The factors significantly associated with rebound were the low level of education of the parents (p=0.012), the administration of medicines to the children by the parents (p=0.000), the long duration of taking the medicines (p=0.021) and poor compliance with treatment (0.000). Conclusions: The rebound in viral load after suppression is a disastrous reality for children. Efforts must be made to strengthen early therapeutic education for children, training of health workers on the process of announcing results and ongoing dialogue with children and adolescents on compliance are ways to improve the maintenance of viral suppression.

930. COVID-19 symptom and viral load rebound among individuals reporting nirmatrelvir/ritonavir use compared to propensity score matched individuals not taking COVID-19 treatment

930. COVID-19 symptom and viral load rebound among individuals reporting nirmatrelvir/ritonavir use compared to propensity score matched individuals not taking COVID-19 treatment

Symptoms, Viral Loads, and Rebound Among COVID-19 Outpatients Treated With Nirmatrelvir/Ritonavir Compared With Propensity Score-Matched Untreated Individuals.

Nirmatrelvir/ritonavir (N/R) reduces severe outcomes from coronavirus disease 2019 (COVID-19); however, rebound after treatment has been reported. We compared symptom and viral dynamics in individuals with COVID-19 who completed N/R treatment and similar untreated individuals. We identified symptomatic participants who tested severe acute respiratory syndrome coronavirus 2-positive and were N/R eligible from a COVID-19 household transmission study. Index cases from ambulatory settings and their households contacts were enrolled. We collected daily symptoms, medication use, and respiratory specimens for quantitative polymerase chain reaction for 10 days during March 2022-May 2023. Participants who completed N/R treatment (treated) were propensity score matched to untreated participants. We compared symptom rebound, viral load (VL) rebound, average daily symptoms, and average daily VL by treatment status measured after N/R treatment completion or 7 days after symptom onset if untreated. Treated (n = 130) and untreated participants (n = 241) had similar baseline characteristics. After treatment completion, treated participants had greater occurrence of symptom rebound (32% vs 20%; P = .009) and VL rebound (27% vs 7%; P < .001). Average daily symptoms were lower among treated participants without symptom rebound (1.0 vs 1.6; P < .01) but not statistically lower with symptom rebound (3.0 vs 3.4; P = .5). Treated participants had lower average daily VLs without VL rebound (0.9 vs 2.6; P < .01) but not statistically lower with VL rebound (4.8 vs 5.1; P = .7). Individuals who completed N/R treatment experienced fewer symptoms and lower VL but rebound occured more often compared with untreated individuals. Providers should prescribe N/R, when indicated, and communicate rebound risk to patients.

Alternative dolutegravir dosing strategies with concurrent rifapentine utilized for latent tuberculosis treatment.

We present a case of a 53-year-old person living with human immunodeficiency virus and a new diagnosis of latent tuberculosis. The patient had baseline suppressed HIV viral load on fixed dose combination dolutegravir/abacavir/lamivudine when once-weekly rifapentine 900mg/isoniazid 900mg/pyridoxine 25mg was initiated for 12weeks. An additional 50mg dolutegravir dose, administered in the evenings, was added to the daily antiretroviral regimen for treatment duration secondary to rifapentine uridine diphosphate glucuronsyl transferase induction. Dolutegravir trough concentrations decreased during concurrent therapy with noted slight HIV viral load rebound. Upon completion of rifapentine use, and a return to dolutegravir 50mg daily dose, the trough concentrations increased with a return to an undetectable viral load. We provide suggested dolutegravir dosing considerations with concomitant rifapentine use, not currently addressed in recommended guidelines.

Viral rebound and safety of nirmatrelvir/ritonavir for lung-transplant recipients infected with SARS-CoV-2

Data on the viral rebound and safety of nirmatrelvir/ritonavir in lung transplant (LTx) recipients are limited. The study prospectively followed four LTx recipients. Clinical characteristics, viral RNA dynamic in throat swabs, and tacrolimus blood concentration were monitored regularly. All four LTx recipients, aged 35–74 years, were not vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). They got coronavirus disease 2019 (COVID-19) after more than one week of admission during the era of Omicron. All cases received nirmatrelvir/ritonavir (NM/r) within two days of infection, and the relative viral RNA copies dropped quickly. Viral load rebound was observed in all four cases after discontinuation of the first five days of NM/r treatment. Three of them received another 5-days antiviral therapy with NM/r. The duration of positive viral PCR testing was 25-28 days. None of them progressed into severe or critical COVID-19. Tacrolimus was stopped 12 h before NM/r and held during the 5-day course of antiviral therapy. Blood concentration of tacrolimus were maintained at a baseline level during these five days. Tacrolimus was re‐initiated at its baseline daily dose 3-4 days after NM/r therapy. However, during the second round of antiviral therapy with NM/r, the concentration of tacrolimus fluctuated wildly. In conclusion, the 5-day course of NM/r treatment was not sufficient for LTx recipients and the viral rebound was common. More data are needed to clarify whether LTx recipients with SARS-CoV-2 viral rebound could benefit from additional treatment with NM/r.

A mathematical model of SARS-CoV-2 immunity predicts paxlovid rebound.

Nirmatrelvir/ritonavir (Paxlovid), an oral antiviral medication targeting SARS-CoV-2, remains an important treatment for COVID-19. Initial studies of nirmatrelvir/ritonavir were performed in SARS-CoV-2 unvaccinated patients without prior confirmed SARS-CoV-2 infection; however, most individuals have now either been vaccinated and/or have experienced SARS-CoV-2 infection. After nirmatrelvir/ritonavir became widely available, reports surfaced of "Paxlovid rebound," a phenomenon in which symptoms (and SARS-CoV-2 test positivity) would initially resolve, but after finishing treatment, symptoms and test positivity would return. We used a previously described parsimonious mathematical model of immunity to SARS-CoV-2 infection to model the effect of nirmatrelvir/ritonavir treatment in unvaccinated and vaccinated patients. Model simulations show that viral rebound after treatment occurs only in vaccinated patients, while unvaccinated (SARS-COV-2 naïve) patients treated with nirmatrelvir/ritonavir do not experience any rebound in viral load. This work suggests that an approach combining parsimonious models of the immune system could be used to gain important insights in the context of emerging pathogens.

Controversies in the Design of Strategies for the Cure of HIV Infection.

The cure for chronic human immunodeficiency virus (HIV) infections has been a goal pursued since the antiretroviral therapy that improved the clinical conditions of patients became available. However, the exclusive use of these drugs is not enough to achieve a cure, since the viral load rebounds when the treatment is discontinued, leading to disease progression. There are several theories and hypotheses about the biological foundations that prevent a cure. The main obstacle appears to be the existence of a latent viral reservoir that cannot be eliminated pharmacologically. This concept is the basis of the new strategies that seek a cure, known as kick and kill. However, there are other lines of study that recognize mechanisms of persistent viral replication in patients under effective treatment, and that would modify the current lines of research on the cure of HIV. Given the importance of these concepts, in this work, we propose to review the most recent evidence on these hypotheses, covering both the evidence that is positioned in favor and against, trying to expose what are some of the challenges that remain to be resolved in this field of research.

A prospective study of predictors of HIV viral load rebound in an HIV hyperendemic rural population of KwaZulu-Natal, South Africa

A prospective study of predictors of HIV viral load rebound in an HIV hyperendemic rural population of KwaZulu-Natal, South Africa

1411. Missed HIV Clinic Visits among Youth Living with HIV in Alabama

Abstract Background Adolescents and young adults with HIV consistently account for about one-fifth of new infections in the United States. YLWH have lower rates of testing, diagnosis, treatment engagement, and viral suppression than adults with HIV. YLWH are particularly challenged with missing medical appointments. Few studies have been published on youth living with HIV (YLWH)’s missed clinic visits and risk factors. Therefore, this study was designed to explore: 1). if the missed visits have significant associations with HIV treatment outcomes (more than 50 counts of CD4 counts drop, viral load increment, and viral suppression) in YLWH; 2). What factors are associated with missed visits for YLWH? 3) Are these factors different from the risk factors of all PLWH? Methods A retrospective study using data records from UAB Family Clinic was designed. The study used the records from March 1st 2020 to August 31st, 2021. Patients aged 16-24 were considered as YLWH. The primary outcomes are missed visits and treatment outcomes. CD4 change, Viral suppression and VL change during the study period were investigated for identifying the association between missed visit and treatment outcome. Age, gender, race, HIV transmission mode, insurance type and the viral suppression in index record were used as factors to predict missed visits. Chi-square test and logistic regression have been conducted in SAS 9.4. Results YLWH with missed visits had more viral load rebound compared to those without missed visits (p=0.04). For YLWH, gender and viral suppression in the index record have significant associations with missed visits (Gender: p=0.03, Viral suppression in index record: p=0.04). In tests among all PLWH, Race (p=0.03), Insurance type (p=0.01) and viral suppression in index record (p=0.001) are associated with missed visits. Table 1.Viral load change by missed visits.Table 2.Risk factors associated with missed visits among YLWH (n=101).Table 3.Risk factors associated with missed visits among PLWY (n=296). Conclusion Missed visits are significantly associated with viral load maintenance, and missed visits have adverse effects on treatment outcomes. Also, the risk factors for YLWH of missed visits are not identical with the risk factors for PLWH from the same cohort. Disclosures All Authors: No reported disclosures.

Safety and efficacy of pharmacotherapy containing INSTIs and chemotherapy drugs in people living with HIV and concomitant colorectal cancer

BackgroundPrevious clinical data have shown that raltegravir-based antiretroviral therapy (ART) with fewer drug-drug interactions (DDIs) and adverse events (AEs) is a good regimen in patients with HIV infection who need cancer chemotherapy. There are currently few data on ART regimens that include Integrase inhibitors (INSTIs) other than RAL among this patient subgroup.MethodsWe evaluated the safety and efficacy of different kinds of INSTI-based regimens among patients with HIV and concomitant colorectal cancer (CRC) who received antineoplastic agents.ResultsFrom January 2020 to November 2021, 66 patients were enrolled. The patients were divided into three groups: 20 patients treated with dolutegravir (DTG)/lamivudine (3TC)/tenofovir (TDF) (group I), 24 patients treated with DTG/albuvirtide (ABT) (group II), and 22 patients treated with bictegravir (BIC)/tenofovir alafenamide (TAF)/emtricitabine (FTC) (group III). The majority of AEs during treatment were of grade 1–2. Treatment‐related AEs of grade 3–4 occurred in 6 patients (9.09%), and no grade 5 AEs occurred. The most common AEs were nausea (100%) and neutrophils (84.85%) attributed to anticancer agents, and there was no significant difference in the incidence of these AEs among the three groups (P > 0.05). Viral load rebound was not observed among pretreated patients during chemotherapy. The viral load of untreated patients who started their ART concomitant with chemotherapy almost decreased to the lower limit of detection 6 months after ART initiation (only one patient in group III had a viral load of 102 copies/ml). At the 6th month, the CD4 count in group I decreased significantly from baseline (P < 0.05). However, the change in CD4 count was not significant in group II (P = 0.457) or group III (P = 0.748).ConclusionsDTG- or BIC-containing regimens are good options for patients with HIV and concomitant CRC.

Expression of type I interferon-associated genes at antiretroviral therapy interruption predicts HIV virological rebound

Although certain individuals with HIV infection can stop antiretroviral therapy (ART) without viral load rebound, the mechanisms under-pinning ‘post-treatment control’ remain unclear. Using RNA-Seq we explored CD4 T cell gene expression to identify evidence of a mechanism that might underpin virological rebound and lead to discovery of associated biomarkers. Fourteen female participants who received 12 months of ART starting from primary HIV infection were sampled at the time of stopping therapy. Two analysis methods (Differential Gene Expression with Gene Set Enrichment Analysis, and Weighted Gene Co-expression Network Analysis) were employed to interrogate CD4+ T cell gene expression data and study pathways enriched in post-treatment controllers versus early rebounders. Using independent analysis tools, expression of genes associated with type I interferon responses were associated with a delayed time to viral rebound following treatment interruption (TI). Expression of four genes identified by Cox-Lasso (ISG15, XAF1, TRIM25 and USP18) was converted to a Risk Score, which associated with rebound (p < 0.01). These data link transcriptomic signatures associated with innate immunity with control following stopping ART. The results from this small sample need to be confirmed in larger trials, but could help define strategies for new therapies and identify new biomarkers for remission.

Post-Paxlovid viral rebound – what do we know and should we be worried?

A small number of patients treated with Pfizer’s antiviral, Paxlovid, for mild-to-moderate COVID-19 infection have been reported to experience a sudden rebound in symptoms and viral load after completing the treatment regimen. The issue is receiving attention in the United States, with some experts advising that healthcare providers should warn patients to watch for COVID-19 […]

HIV continuum of care: bridging cross-sectional and longitudinal analyses.

The aim of this study was to propose a unified continuum-of-care (CoC) analysis combining cross-sectional and longitudinal elements, incorporating time spent between stages. The established 90-90-90 target follows a cross-sectional four-stage CoC analysis, lacking information on timing of diagnosis, antiretroviral therapy (ART) initiation, and viral suppression durability. Data were derived from the Athens Multicenter AIDS Cohort Study (AMACS). In the cross-sectional CoC, we added stratification of diagnosed people with HIV (PWH) by estimated time from infection to diagnosis; of those who ever initiated ART or achieved viral suppression by corresponding current status (in 2018); and cumulative incidence function (CIF) of ART initiation and viral suppression, treating loss-to-follow-up (LTFU) as competing event. Viral suppression was defined as viral load less than 500 copies/ml. Viral suppression durability was assessed by the CIF of viral load rebound. About 89.1% of PWH in 2018 were diagnosed (range of diagnoses: 1980-2018). Median time to diagnosis was 3.5 years (IQR: 1.1-7.0). Among diagnosed, 89.1% were ever treated, of whom 86.7% remained on ART. CIF of ART initiation and LTFU before ART initiation were 80.9 and 6.0% at 5 years since diagnosis, respectively. Among treated, 89.4% achieved viral suppression, of whom 87.4% were currently virally suppressed. The CIF of viral load rebound was 24.2% at 5 years since first viral suppression but substantially reduced in more recent years. The proposed analysis highlights time gaps in CoC not evident by the standard cross-sectional approach. Our analysis highlights the need for early diagnosis and identifies late presenters as a key population for interventions that could decrease gaps in the CoC.

Influence of treatment with neutralizing monoclonal antibodies on the SARS-CoV-2 nasopharyngeal load and quasispecies

ObjectivesTo evaluate the impact of neutralizing monoclonal antibody (mAb) treatment and to determine whether the selective pressure of mAbs could facilitate the proliferation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with spike protein mutations that might attenuate mAb effectiveness. Patients and methodsWe evaluated the impact of mAbs on the nasopharyngeal (NP) viral load and virus quasispecies of mAb-treated patients using single-molecule real-time sequencing. The mAbs used were: Bamlanivimab alone (four patients), Bamlanivimab/Etesevimab (23 patients) and Casirivimab/Imdevimab (five patients). ResultsThe NP SARS-CoV-2 viral load of mAb-treated patients decreased from 8.2 log10 copies/mL before administration to 4.3 log10 copies/mL 7 days after administration. Five immunocompromised patients given Bamlanivimab/Etesevimab were found to have mAb activity-reducing spike mutations. Two patients harboured SARS-CoV-2 variants with a Q493R spike mutation 7 days after administration, as did a third patient 14 days after administration. The fourth patient harboured a variant with a Q493K spike mutation 7 days post-treatment, and the fifth patient had a variant with a E484K spike mutation on day 21. The emergence of the spike mutation was accompanied by stabilization or rebound of the NP viral load in three of five patients. ConclusionTwo-mAb therapy can drive the selection of resistant SARS-CoV-2 variants in immunocompromised patients. Patients given mAbs should be closely monitored and measures to limit virus spread should be reinforced.