Clinical Relevance of Absolute BK Polyoma Viral Load Kinetics in Patients With Biopsy Proven BK Polyomavirus Associated Nephropathy

Introduction: The absolute BK viral load is an important diagnostic surrogate for BK polyomavirus associated nephropathy (PyVAN) after renal transplant (KTX) and serial assessment of BK viremia is recommended. However, there is no data indicating which particular viral load change, i.e., absolute vs. relative viral load changes (copies/ml; percentage of the preceding viremia) is associated with worse renal graft outcomes.Materials and Methods: In this retrospective study of 91 biopsy proven PyVAN, we analyzed the interplay of exposure time, absolute and relative viral load kinetics, baseline risk, and treatment strategies as risk factors for graft loss after 2 years using a multivariable Poisson-model.Results: We compared two major treatment strategies: standardized immunosuppression (IS) reduction (n = 53) and leflunomide (n = 30). The median viral load at the index biopsy was 2.15E+04 copies/ml (interquartile range [IQR] 1.70E+03–1.77E+05) and median peak viremia was 3.6E+04 copies/ml (IQR 2.7E+03–3.3E+05). Treatment strategies and IS-levels were not related to graft loss. After correction for baseline viral load and estimated glomerular filtration rate (eGFR), absolute viral load decrease/unit remained an independent risk factor for graft loss [incidence rate ratios [IRR] = 0.77, (95% CI 0.61–0.96), p = 0.02].Conclusion: This study provides evidence for the prognostic importance of absolute BK viremia kinetics as a dynamic parameter indicating short-term graft survival independently of other established risk factors.

Dolutegravir plus lamivudine versus efavirenz plus tenofovir disoproxil fumarate and lamivudine in antiretroviral-naive adults with HIV-1 infection

Background Concerns regarding potential toxicity and drug-drug interactions during long-term treatment with three-drug active antiretroviral therapy (ART) regimens have been attracting increasing attention. We aimed to evaluate the efficacy and safety of dolutegravir (DTG) plus lamivudine (3TC) in ART-naive adults in China. Methods This prospective observational cohort study enrolled HIV-naive inpatients treated with DTG + 3TC (2DR arm) or efavirenz (EFV) plus tenofovir disoproxil fumarate (TDF) and 3TC (3DR arm). There were no limits on baseline viral load. Inflammatory biomarkers were also investigated in the 2DR arm. Results Between September 2019 and January 2020, 27 patients treated with DTG + 3TC and 28 patients treated with EFV + TDF + 3TC were enrolled in the study. At week 12, the proportion of patients with viral loads < 50 copies/mL in the 2DR arm was 81.5% (22/27) compared with 53.6% (15/28) in the 3DR arm (p < 0.01). At week 24, the proportion of patients with viral loads < 50 copies/mL in the 2DR arm was 100% (26/26) compared with 83.3% (20/24) in the 3DR arm (p < 0.05). Mean changes in CD4 cell counts from baseline at week 12 were 125.46 cells/µL in the 2DR arm and 41.20 cells/µL in the 3DR arm (p < 0.05). Mean changes in CD4 cell counts from baseline at week 24 were 209.68 cells/µL in the 2DR arm and 73.28 cells/µL in the 3DR arm (p < 0.05). Conclusions DTG + 3TC achieved virologic suppression more rapidly than EFV + TDF + 3TC after 12 and 24 weeks. DTG + 3TC could represent an optimal regimen for advanced patients. Clinical Trial Registration ChiCTR1900027640 (22/November/2019).

A Quantitative Systems Pharmacology Model of the Pathophysiology and Treatment of COVID-19 Predicts Optimal Timing of Pharmacological Interventions

A quantitative systems pharmacology (QSP) model of the pathogenesis and treatment of SARS-CoV-2 infection can streamline and accelerate the development of novel medicines to treat COVID-19. Simulation of clinical trials allows in silico exploration of the uncertainties of clinical trial design and can rapidly inform their protocols. We previously published a preliminary model of the immune response to SARS-CoV-2 infection. To further our understanding of COVID-19 and treatment we significantly updated the model by matching a curated dataset spanning viral load and immune responses in plasma and lung. We identified a population of parameter sets to generate heterogeneity in pathophysiology and treatment and tested this model against published reports from interventional SARS-CoV-2 targeting Ab and anti-viral trials. Upon generation and selection of a virtual population, we match both the placebo and treated responses in viral load in these trials. We extended the model to predict the rate of hospitalization or death within a population. Via comparison of the in silico predictions with clinical data, we hypothesize that the immune response to virus is log-linear over a wide range of viral load. To validate this approach, we show the model matches a published subgroup analysis, sorted by baseline viral load, of patients treated with neutralizing Abs. By simulating intervention at different timepoints post infection, the model predicts efficacy is not sensitive to interventions within five days of symptom onset, but efficacy is dramatically reduced if more than five days pass post-symptom onset prior to treatment.

Long-term safety, tolerability and antiviral activity of rilpivirine in antiretroviral-naïve adolescents living with HIV-1, aged 12 to less than 18 years: Week 240 findings of a phase 2, open-label study, PAINT

Introduction: This Phase-2 study investigated long-term safety and efficacy of rilpivirine (RPV)+two investigator-selected nucleos(t)ide reverse-transcriptase inhibitors (NRTIs), in HIV-1-infected antiviral therapy-naïve adolescents. Methods: Participants (≥12to <18 years) were treated with RPV 25mg qd+2 NRTIs who entered treatment extension period for up to 240 weeks with visits every 3 months. Long-term safety (analysis of adverse events [AEs], laboratory results), efficacy (virologic-response and outcome for patients with viral load <50 and <400 by time to loss of virologic-response (TLOVR) and FDA Snapshot methods, and CD4+ cell count), and adherence (by pill-count) for up to 240 weeks are presented. Results: 24 of 36 entered treatment extension period and 21 completed week 240. At week 240, viral load <50 copies/mL was achieved by 14/32 (43.8%) participants; virologic-response by TLOVR was higher in participants with baseline viral load≤100,000 copies/mL (48.0%) versus viral load >100,000 copies/mL (28.6%). By FDA Snapshot, viral load < 50 copies/mL at week 240 was 53.1% (17/32) in participants with baseline viral load ≤100,000 copies/mL. Higher response was observed in participants with adherence >95% and baseline viral load ≤100,000 copies/mL. Through week 240, 16/32 participants (50.0%) experienced virologic-failure, including seven who developed treatment-emergent RPV resistance-associated mutations (RAMs; frequently E138K); all 7 had ≥1 treatment-emergent NRTI RAM. No serious AEs after week 48, no discontinuations due to AEs between week 48 and week 240 and no new safety signals were observed. RPV did not affect pubertal development/adolescent growth. Conclusions: At the 5-year follow-up, efficacy was low in adolescents, particularly those with poor adherence and/or high baseline viral load >100,000 copies/mL. To limit the risk of virologic failure, Edurant is restricted to patients with a baseline VL ≤100,000 copies/mL in most countries. In addition, adequate treatment adherence to RPV treatment is imperative for long-term viral suppression and should be emphasized in the management of adolescents living with HIV. RPV exhibited favorable long-term safety profile for adolescents living with HIV-1 with adequate adherence. Clinical Trial Number: NCT00799864

REGEN-COV for the Treatment of Hospitalized Patients with Covid-19

Background: Hospitalized patients with Covid-19 experience high mortality rates, ranging from 10-30%. Casirivimab and imdevimab (REGEN-COV) is authorized in various jurisdictions for use in outpatients with Covid-19 and in post-exposure prophylaxis. The UK-based platform RECOVERY study reported improved survival in hospitalized seronegative patients treated with REGEN-COV, but in most of the world, anti-spike monoclonal antibody therapy is currently not approved for use in hospitalized patients. Methods: In this phase 1/2/3 double-blind placebo-controlled trial, patients on low-flow or no supplemental oxygen hospitalized with Covid-19 were randomized (1:1:1) to 2.4 g or 8.0 g REGEN-COV or placebo and characterized at baseline for viral load and SARS-CoV-2 endogenous immune response. Results: 1336 patients on low-flow or no supplemental oxygen were treated. The primary endpoint was met: in seronegative patients, the LS mean difference (REGEN-COV vs. placebo) for TWA change from baseline viral load was -0.28 log10 copies/mL (95% CI: -0.51, -0.05; P=0.0172). The primary clinical analysis of death or mechanical ventilation from day 6-29 in patients with high-viral load had a strong positive trend but did not reach significance. REGEN-COV reduced all-cause mortality in seronegative patients through day 29 (RRR, 55.6%; 95% CI: 24.2%, 74%). No safety concerns were noted overall nor in seropositive patients. Conclusions: In hospitalized patients with Covid-19 on low-flow or no oxygen, REGEN-COV treatment reduced viral load and the risk of death or mechanical ventilation as well as all-cause mortality in the overall population, with the benefit driven by seronegative patients and no harm observed in seropositive patients. (ClinicalTrials.gov number, NCT04426695.)

75. High Rates of Virologic Suppression with DTG/3TC in Newly Diagnosed Adults with HIV-1 Infection and Baseline Viral Load >500,000 c/mL: 48-Week Subgroup Analysis of the STAT Study

Background The primary analysis of the STAT study demonstrated the feasibility, efficacy, and safety of using DTG/3TC as a first-line regimen in a test-and-treat setting through 24 weeks, with therapy adjustments for baseline resistance or hepatitis B virus (HBV) co-infection. Here we present secondary analyses through Week 48 of virologic outcomes in participants by baseline viral load (VL). Methods STAT is a single-arm study of treatment-naive adults with HIV-1 infection who initiated DTG/3TC ≤ 14 days after HIV-1 diagnosis without availability of screening/baseline laboratory results. If baseline testing indicated DTG or 3TC resistance, HBV co-infection, or creatinine clearance &lt; 30 mL/min/1.73 m2, then antiretroviral therapy (ART) was potentially adjusted and participants remained on study. Efficacy analyses included proportion of participants with HIV-1 RNA &lt; 50 c/mL regardless of ART regimen at Week 48, among all participants (ITT-E missing = failure analysis) and among participants with available HIV-1 RNA data at Week 48 (observed analysis). Results Of 131 enrolled, DTG/3TC treatment was adjusted in 10 participants, and of those with available data (n=7), all (100%) achieved HIV-1 RNA &lt; 50 c/mL at Week 48. At Week 48, 82% (107/131) of all participants (Figure 1) and 97% (107/110) of those with available data (Figure 2) achieved HIV-1 RNA &lt; 50 c/mL. Of participants with baseline VL ≥ 500,000 c/mL, 89% (17/19) achieved HIV-1 RNA &lt; 50 c/mL at Week 48; the remaining 2 withdrew from study. Of participants with baseline VL ≥ 1,000,000 c/mL, 90% (9/10) achieved HIV-1 RNA &lt; 50 c/mL at Week 48 (Table); the remaining participant withdrew consent. Of the 17 participants with baseline VL ≥ 500,000 c/mL with available data through Week 48, 76% (13/17) achieved virologic suppression by Week 24. One participant with baseline VL ≥ 500,000 c/mL switched from DTG/3TC before the Week 48 assessment. Of the 9 participants with baseline VL ≥ 1,000,000 c/mL with available data through Week 48, most participants (8/9; 89%) were suppressed by Week 24. Figure 1. Virologic outcomes at Week 48, overall and by baseline VL and CD4+ cell count: ITT-E missing = failure analysis. Figure 2. Virologic outcomes at Week 48, overall and by baseline VL and CD4+ cell count: observed analysis. Table. Viral Load by Study Visit Among Participants with Baseline HIV-1 RNA ≥1,000,000 c/mL Conclusion These data provide evidence for the efficacy and feasibility of using DTG/3TC as a first-line regimen in a test-and-treat setting, including among participants with very high baseline VL. Disclosures Charlotte-Paige M. Rolle, MD MPH, Gilead Sciences (Grant/Research Support, Scientific Research Study Investigator, Speaker’s Bureau)Janssen Infectious Disease (Scientific Research Study Investigator, Advisor or Review Panel member)ViiV Healthcare (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker's Bureau) Tulika Singh, MD MS AAHIVS, Gilead (Grant/Research Support, Advisor or Review Panel member)ViiV (Grant/Research Support, Advisor or Review Panel member, Speaker's Bureau) Moti Ramgopal, MD FIDSA, Abbvie (Scientific Research Study Investigator, Speaker's Bureau)Gilead (Consultant, Scientific Research Study Investigator, Speaker's Bureau)Janssen (Consultant, Scientific Research Study Investigator, Research Grant or Support, Speaker's Bureau)Merck (Consultant, Scientific Research Study Investigator)ViiV (Consultant, Scientific Research Study Investigator, Speaker's Bureau) Dushyantha Jayaweera, MD, mrcog(uk), face, Gilead (Research Grant or Support)Janssen (Research Grant or Support)viiv (Research Grant or Support) Peter Leone, MD, viiv healthcare (Employee) Jessica Matthews, BS, ViiV Healthcare (Employee) Michael Cupo, Ph.D., GlaxoSmithKline (Employee) Mark Underwood, PhD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Kostas Angelis, PhD, GSK (Employee, Shareholder) Brian Wynne, MD, ViiV Healthcare (Employee, Shareholder, I have shares in GSK, the part owner of ViiV) Deanna Merrill, PharmD, MBA, AAHIVP, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Christopher T. Nguyen, MD, ViiV Healthcare (Employee) Jean A. van Wyk, MB,ChB, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Andrew Zolopa, MD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee)

Diagnostic approach to elucidate the efficacy and side effects of direct-acting antivirals in HCV infected patients

Introduction: The conventional interferon therapy of hepatitis C virus has been substituted substantially with sofosbuvir and daclatasvir due to constraints in efficacy and tolerability. This study aimed diagnostically to monitor the effectiveness and side effects of direct-acting antivirals in the management of HCV infections. Methodology: This prospective study was conducted on HCV-infected patients treated with sofosbuvir and daclatasvir. Different serological, biochemical, hematological, and molecular techniques were used for the assessment of patients. Only treatment-naive patients aged ≥ 18 to 75 years received 12 weeks of treatment. The primary endpoint was a sustained virologic response with undetectable HCV RNA in the patients’ serum at the end of the treatment. Results: We identified 229 cases of confirmed HCV infections by PCR, 94.3% of which had genotype 3. The study population comprised 66% females and 34% males with a median age of 42.2 ± 10.6 SD. Ninety-three percent of the patients accomplished SVR at week 12. The combined therapy of SOF/DAC achieved the highest efficacy rate (92.6%) among the different HCV genotype 3 patients. A statistically significant relationship was observed between low baseline viral load (p < 0.001; 95% CI = 1.2-3.1) and HCV genotype 3 with minor side effects, including lethargy, headache, nausea, insomnia, diarrhea, and fever. Conclusions: HCV-infected patients can be treated well with an interferon-free SOF/DAC regimen, tolerated with generally mild adverse effects with a higher SVR.

Factors Associated With Viral Suppression and Rebound Among HIV Patients On Treatment: A Retrospective Study in Ghana

Background Viral suppression remains the most desired outcome in the management of patients with Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS) and this can be achieved by an effective combined Antiretroviral Therapy (cART). However, some patients who achieve viral suppression may experience viral rebound with dire consequence. We evaluated viral suppression and rebound and their associated factors among adult patients on cART in Kumasi, Ghana. Methods This hospital-based retrospective study was conducted at the Komfo Anokye Teaching Hospital in Ghana. We reviewed the medical records of 720 HIV patients on cART. Statistical analyses were performed using SPSS Version 26.0 and GraphPad prism version 8.0. P<0.05 was considered statistically significant. Results Proportions of patients with viral suppression and viral rebound were 76.1% and 21.0% respectively. Being diagnosed at WHO stage I [aOR=4.26, 95%CI (4.20-48.44), p<0.0001], having good adherence to ART [aOR=5.64, 95%CI (2.86-11.13), p<0.0001], taking Nevirapine-based regimen [aOR=4.66, 95%CI (1.20-18.04), p=0.0260] and increasing duration of treatment (p<0.0001) were independently associated with higher odds of viral suppression. However, being diagnosed at WHO stage II (aOR=7.39, 95%CI: 2.67-20.51; p<0.0001) and stage III (aOR=8.62, 95%CI: 3.16-23.50; p<0.0001), having poor adherence (aOR=175.48, 95%CI: 44.30-695.07; p<0.0001), recording baseline suppression value of 20-49 copies/mL (aOR=6.43, 95%CI: 2.72-15.17; p<0.0001) and being treated with Zidovudine/Lamivudine/Efavirenz (aOR=6.49, 95%CI: 1.85-22.79; p=0.004) and Zidovudine/Lamivudine/Nevirapine (aOR=18.68, 95% CI: 1.58-220.90; p=0.02) were independently associated with higher odds of viral rebound. Conclusion Approximately 76% viral suppression rate among HIV patients on cART in Kumasi falls below the WHO 95% target by the year 2030. Choice of ART combination, drug adherence, WHO clinical staging and baseline viral load are factors associated with suppression or rebound. These clinical characteristics of HIV patients must be monitored concurrently with the viral load.

Does Rapid Initiation of Antiretroviral Therapy At HIV Diagnosis Impact On Virological Response in a Real-Life Setting? A Single Centre Experience in Northern Italy

Background Rapid initiation of antiretroviral therapy (ART) has been largely proven efficacious and safe mostly through clinical trials. Further investigations are needed to better define feasibility and acceptability of rapid ART approach in real-life settings. Methods We conducted a retrospective, observational study on newly HIV-diagnosed patients referred to Infectious and Tropical Diseases department of ASST Spedali Civili Hospital of Brescia from September 1st, 2015, to July 31st, 2019. All patients’ baseline characteristics were anonymously extracted from medical records. According to the timing of ART initiation, we distinguished 3 groups of patients (rapid, intermediate and late group) and represented the trend of virological response during a 400 day-period. The hazard ratios of each predictor on viral suppression (HIV RNA < 50 copies/ml) were estimated through Cox proportional hazard model. Results Median time from HIV diagnosis to first medical referral was 15 days and median time from first HIV care access to therapy start was 24 days. Three groups of patients were differentiated depending on ART initiation: within 7 days (rapid group, 37.6%), between 8 and 30 days (intermediate group, 20.6%) and after 30 days (late group, 41.8%). Longer time to ART start and higher baseline viral load were associated with a reduced probability of viral suppression. After one year, all groups showed high viral suppression rate (99%). Conclusions In high-income setting as Italy, rapid ART approach seems to be useful to accelerate time to viral suppression. The latter tends to be great over time regardless the timing of ART initiation.

Additive quantile mixed effects modelling with application to longitudinal CD4 count data

Quantile regression offers an invaluable tool to discern effects that would be missed by other conventional regression models, which are solely based on modeling conditional mean. Quantile regression for mixed-effects models has become practical for longitudinal data analysis due to the recent computational advances and the ready availability of efficient linear programming algorithms. Recently, quantile regression has also been extended to additive mixed-effects models, providing an efficient and flexible framework for nonparametric as well as parametric longitudinal forms of data analysis focused on features of the outcome beyond its central tendency. This study applies the additive quantile mixed model to analyze the longitudinal CD4 count of HIV-infected patients enrolled in a follow-up study at the Centre of the AIDS Programme of Research in South Africa. The objective of the study is to justify how the procedure developed can obtain robust nonlinear and linear effects at different conditional distribution locations. With respect to time and baseline BMI effect, the study shows a significant nonlinear effect on CD4 count across all fitted quantiles. Furthermore, across all fitted quantiles, the effect of the parametric covariates of baseline viral load, place of residence, and the number of sexual partners was found to be major significant factors on the progression of patients’ CD4 count who had been initiated on the Highly Active Antiretroviral Therapy study.