Ruxolitinib is a US Food and Drug Administration–approved orally administered Janus kinase (1/2) inhibitor that reduces cytokine-induced inflammation. As part of a randomized, phase 2, open-label trial, ruxolitinib (10 mg twice daily) was administered to HIV-positive, virologically suppressed individuals (33 men, 7 women) on antiretroviral therapy (ART) for 5 weeks. Herein, we report the population PK subsequently determined from this study. Plasma concentrations of ruxolitinib (294 samples) and antiretroviral agents were measured at week 1 (N = 39 participants) and week 4 or 5 (N = 37). Ruxolitinib PK was adequately described with a 2-compartment model with first-order absorption and elimination with distribution volumes normalized to mean body weight (91.5 kg) and a separate typical clearance for participants administered efavirenz (a known cytochrome P450 3A4 inducer). Participants administered an ART regimen with efavirenz had an elevated typical apparent oral clearance versus the integrase inhibitor regimen group (22.5 vs 12.9 L/hr; N = 14 vs 25). Post hoc predicted apparent oral clearance was likewise more variable and higher (P <.0001) in those administered efavirenz. There was an ≈25% variation in ruxolitinib plasma exposures between week 1 and week 4/5. ART plasma concentrations resembled those from PK studies without ruxolitinib. Therefore, integrase inhibitor–based ART regimens may be preferred over efavirenz-based regimens when ruxolitinib is administered to HIV-positive individuals.

Vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection wanes over time, requiring updated boosters. In a phase 2, open-label, randomized clinical trial with sequentially enrolled stages at 22 US sites, we assessed safety and immunogenicity of a second boost with monovalent or bivalent variant vaccines from mRNA and protein-based platforms targeting wild-type, Beta, Delta and Omicron BA.1 spike antigens. The primary outcome was pseudovirus neutralization titers at 50% inhibitory dilution (ID50 titers) with 95% confidence intervals against different SARS-CoV-2 strains. The secondary outcome assessed safety by solicited local and systemic adverse events (AEs), unsolicited AEs, serious AEs and AEs of special interest. Boosting with prototype/wild-type vaccines produced numerically lower ID50 titers than any variant-containing vaccine against all variants. Conversely, boosting with a variant vaccine excluding prototype was not associated with decreased neutralization against D614G. Omicron BA.1 or Beta monovalent vaccines were nearly equivalent to Omicron BA.1 + prototype or Beta + prototype bivalent vaccines for neutralization of Beta, Omicron BA.1 and Omicron BA.4/5, although they were lower for contemporaneous Omicron subvariants. Safety was similar across arms and stages and comparable to previous reports. Our study shows that updated vaccines targeting Beta or Omicron BA.1 provide broadly crossprotective neutralizing antibody responses against diverse SARS-CoV-2 variants without sacrificing immunity to the ancestral strain. ClinicalTrials.gov registration: NCT05289037 .

Background: Lopinavir (LPV)/ritonavir (RTV) co-formulation (LPV/RTV) is a widely used protease inhibitor (PI)-based regimen to treat HIV-infection. As with all PIs, the trough concentration (C trough) is a primary determinant of response, but the optimum exposure remains poorly defined. The primary objective was to develop an integrated LPV population pharmacokinetic model to investigate the influence of α-1-acid glycoprotein and link total and free LPV exposure to pharmacodynamic changes in HIV-1 RNA and assess viral dynamic and drug efficacy parameters. Methods: Data from 35 treatment-naïve HIV-infected patients initiating therapy with LPV/RTV 400/100 mg orally twice daily across two studies were used for model development and simulations using ADAPT. Total LPV (LPVt) and RTV concentrations were measured by high-performance liquid chromatography with ultraviolet (UV) detection. Free LPV (LPVf) concentrations were measured using equilibrium dialysis and mass spectrometry. Results: The LPVt typical value of clearance ( CLLPVt/F) was 4.73 L/h and the distribution volume (V LPVt) was 55.7 L. The clearance ( CL LPVt/F) and distribution volume (V fF) for LPVf were 596 L/h and 6,370 L, respectively. The virion clearance rate was 0.0350 h-1. The simulated LPVLPVttrough values at 90 % (EC90) and 95 % (EC95) of the maximum response were 316 and 726 ng/mL, respectively. Conclusions: The pharmacokinetic-pharmacodynamic model provides a useful tool to quantitatively describe the relationship between LPV/RTV exposure and viral response. This comprehensive modelling and simulation approach could be used as a surrogate assessment of antiretroviral (ARV) activity where adequate early-phase dose-ranging studies are lacking in order to define target trough concentrations and possibly refine dosing recommendations.

This study compared HIV-1 genotypes shed over time (≤3.5 years) in the vaginal secretions (VS) and blood plasma (BP) of 15 chronically infected women. Analysis of predicted coreceptor tropism (CCR5=R5, CXCR4=X4) for quasispecies shedding revealed three patterns: (1) viral quasispecies shed in both VS and BP were restricted to R5-tropism at all time points, (2) quasispecies shed in VS were restricted to R5-tropism at all time points but X4 quasispecies were identified in the BP at one or more time points, and (3) quasispecies shed in matched VS and BP both contained X4-tropic viruses. Overall, the frequency of X4 quasispecies circulation in VS was 2-fold less than in BP and detection of X4 virus in VS was more likely to occur when X4 quasispecies comprised more than 50% of BP viruses (p=0.01) and when declines in blood CD4 + lymphocyte levels were the greatest (p=0.038). Additionally, the mean number of predicted N-glycosylation sites between matched VS and BP samples was strongly correlated (r=0.86, p < 0.0001) with glycosylation densities in the following order (VS R5=BP R5 > BP X4 > VS X4). The X4 glycosylation densities may result from compartmentalization pressures in the female genital tract or the delayed appearance of these viruses in VS. Our results suggest that the presence of X4 virus in VS is associated with a threshold population of X4 quasispecies in BP, which are increasing during the HIV-induced failure of the human immune system.

Initiation of antiretroviral therapy during acute HIV-1 infection may prevent persistent immune activation. We analyzed longitudinal CD38+HLA-DR+ CD8+ T-cell percentages in 31 acutely infected individuals who started early (median 43 days since infection) and successful antiretroviral therapy, and maintained viral suppression through 96 weeks. Pretherapy a median of 72.6% CD8+ T cells were CD38+HLA-DR+, and although this decreased to 15.6% by 96 weeks, it remained substantially higher than seronegative controls (median 8.9%, P = 0.008). Shorter time to suppression predicted lower activation at 96 weeks. These results support the hypothesis that very early events in HIV-1 pathogenesis may result in prolonged immune dysfunction.

HIV-1 protease inhibitors (PIs) exhibit different protein binding affinities and achieve variable plasma and tissue concentrations. Degree of plasma protein binding may impact central nervous system penetration. This cross-sectional study assessed cerebrospinal fluid (CSF) unbound PI concentrations, HIV-1 RNA, and neopterin levels in subjects receiving either ritonavir-boosted darunavir (DRV), 95% plasma protein bound, or atazanavir (ATV), 86% bound. Unbound PI trough concentrations were measured using rapid equilibrium dialysis and liquid chromatography/tandem mass spectrometry. Plasma and CSF HIV-1 RNA and neopterin were measured by Ampliprep/COBAS® Taqman® 2.0 assay (Roche) and enzyme-linked immunosorbent assay (ALPCO), respectively. CSF/plasma unbound drug concentration ratio was higher for ATV, 0.09 [95% confidence interval (CI) 0.06-0.12] than DRV, 0.04 (95%CI 0.03-0.06). Unbound CSF concentrations were lower than protein adjusted wild-type inhibitory concentration-50 (IC50) in all ATV and 1 DRV-treated subjects (P<0.001). CSF HIV-1 RNA was detected in 2/15 ATV and 4/15 DRV subjects (P=0.65). CSF neopterin levels were low and similar between arms. ATV relative to DRV had higher CSF/plasma unbound drug ratio. Low CSF HIV-1 RNA and neopterin suggest that both regimens resulted in CSF virologic suppression and controlled inflammation.

Background Immune mediated changes in circulating α-1-acid glycoprotein (AAG), a type 1 acute phase protein, which binds protease inhibitors (PI), may alter protein binding and contribute to PI's pharmacokinetic (PK) variability. Methods In a prospective, 2-phase intensive PK study on antiretroviral naive human immunodeficiency virus (HIV)-infected subjects treated with a lopinavir-/ritonavir-based regimen, steady state PK sampling and AAG assays were performed at weeks 2 and 16 of treatment. Results Median entry age was 43 years (n = 16). Median plasma log10 HIV-1 RNA, CD4 T-cell counts, and AAG were 5.16 copies/mL, 28 cells/μL, and 143 mg/dL, respectively.The total lopinavir area under the concentration time curve (AUC12_total) and maximum concentration (Cmax_total) changed linearly with AAG at mean rates of 16±7 mg*hr/L (slope ± SE); P = .04, and 1.6 ± 0.6 mg/L, P = .02, per 100 mg/dL increase in AAG levels, respectively (n = 15).A 29% drop in AAG levels between week 2 and week 16 was associated with 14% (geometric mean ratio [GMR] = 0.86; 90% confidence interval [CI] = 0.74-0.98) and 13% (GMR = 0.87; 90% CI = 0.79-0.95) reduction in AUC12_total and Cmax_total, respectively. Neither free lopinavir PK parameters nor antiviral activity (HIV-1 RNA average AUC minus baseline) was affected by change in plasma AAG. Conclusions Changes in plasma AAG levels alter total lopinavir concentrations, but not the free lopinavir exposure or antiviral activity. This observation may have implications in therapeutic drug monitoring.

Study Objective To evaluate the pharmacokinetic compatibility of a ritonavir-boosted indinavir-fosamprenavir combination among patients with human immunodeficiency virus (HIV). Design Single-center, nonrandomized, prospective, multiple-dose, two-phase pharmacokinetic study. Setting University research center. Patients Eight adult patients with HIV infection who had been receiving and tolerating indinavir 800 mg–ritonavir 100 mg twice/day for at least 2 weeks. Intervention After 12-hour pharmacokinetic sampling was performed on all patients (period A), fosamprenavir (a prodrug of amprenavir) 700 mg twice/day was coadministered for 5 days, with a repeat 12-hour pharmacokinetic sampling performed on the fifth day (period B). Measurements and Main Results Pharmacokinetic parameters were determined for indinavir, ritonavir, and amprenavir: area under the concentration-time curve from time 0 to 12 hours after dosing (AUC0–12), maximum plasma concentration (Cmax), and 12-hour plasma concentration (C12). For each parameter, the geometric mean, as well as the geometric mean ratio (GMR) comparing period B with period A, were calculated. Indinavir Cmax was lowered by 20% (GMR 0.80, 95% confidence interval [CI] 0.67–0.96), AUC0–12 was lowered by 6% (GMR 0.94, 95% CI 0.74–1.21), and C12 was increased by 28% (GMR 1.28, 95% CI 0.78–2.10). Ritonavir AUC0–12 was 20% lower (GMR 0.80, 95% CI 0.54–1.19), Cmax was 15% lower (GMR 0.85, 95% CI 0.55–1.32), and C12 was 7% lower (GMR 0.93, 95% CI 0.49–1.76). With the exception of indinavir Cmax, the changes in indinavir and ritonavir pharmacokinetic parameters observed after fosamprenavir coadministration were not statistically significant. The geometric means of amprenavir AUC0–12, Cmax, and C12 were 41,517 ng•hour/ml (95% CI 30,317–56,854 ng•hr/ml), 5572 ng/ml (95% CI 4330–7170 ng/ml), and 2421 ng/ml (95% CI 1578–3712 ng/ml), respectively. Conclusion The combination of indinavir 800 mg–ritonavir 100 mg–fosamprenavir 700 mg twice/day appears to be devoid of a clinically significant drug-drug interaction and should be evaluated as an alternative regimen in salvage HIV treatment. This combination may be suitable as part of a background regimen to optimize the therapeutic benefit of newer classes of antiretroviral agents such as the integrase and coreceptor inhibitors in the treatment of multidrug-resistant viruses.

Objectives Because liver enzymes elevation (LEE) complicates antiretroviral (ARV) therapy, and because the strongest risk factor for ARV-related LEE is HBV/HCV coinfection, it is speculated that ARV-related LEE may be a form of immune reconstitution disease. This study summarizes the relation between immune reconstitution, ARV-induced LEE, and HBV/HCV coinfection. Methods Medical records of ARV-naïve HIV-infected patients initiating ARV were reviewed for hepatitis coinfection, LEE (grade ≥2 AST/ALT) and changes in CD4 T-cell counts over time in an urban HIV clinic. Risk factors for LEE were statistically evaluated, and changes in CD4 T-cell counts were estimated by a mixed-effects linear model. Results Predictors of LEE included HBV/HCV coinfection (OR = 6.44) and stavudine use (OR = 2.33). Nelfinavir use was protective (OR = 0.45). The mean rate of change in CD4 T-cell counts was higher in HBV/HCV coinfected subjects who developed LEE (99 cells/μL per month) compared with non-coinfected subjects who did not develop LEE (59 cells/μL per month, P = 0.03), non-coinfected subjects who developed LEE (36 cells/μL per month, P = 0.01), and coinfected subjects who did not develop LEE, 38% higher (62 cells/μL per month; P = 0.11) Conclusions A more robust immune restoration was observed among HBV/HCV coinfected subjects who developed liver enzyme elevation after antiretroviral initiation compared with other groups. This finding suggests that ARV-related liver enzyme elevation may be related in part to immune reconstitution, as measured by changes in CD4 T-cell counts.

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.