Clinical investigators were sent an urgent letter requesting that all participants stop randomised drug treatment within 48 h. This decision was initially made because of severe, yet reversible, ...liver toxicity in at least one patient, and asymptomatic rises in liver enzymes in several other patients. For the motivated treatment-naive individual infected with drug-susceptible HIV, as few as two pills taken once a day will result in durable and perhaps permanent suppression of HIV to undetectable levels.7 The long-term prognosis for these patients is now so favourable that many organisations, including the community-based European AIDS Treatment Group,8 heavily criticised GSK and other drug companies for performing a study that randomises treatment-naive patients to a potentially unsafe drug such as aplaviroc. In controlled clinical studies, current regimens routinely suppress HIV RNA levels to undetectable levels for long periods, with overall success rates of over 80% reported with conservative intent-to-treat analytic techniques (many "failures" in these studies are due to reasons other than virological rebound).11,12 These virological success rates are so high that any new regimen must achieve and maintain undetectable viral loads in the vast majority of patients.
Cannabinoid use could potentially alter HIV RNA levels by two mechanisms: immune modulation or cannabinoid-protease inhibitor interactions (because both share cytochrome P-450 metabolic pathways).
To ...determine the short-term effects of smoked marijuana on the viral load in HIV-infected patients.
Randomized, placebo-controlled, 21-day intervention trial.
The inpatient General Clinical Research Center at the San Francisco General Hospital, San Francisco, California.
67 patients with HIV-1 infection.
Participants were randomly assigned to a 3.95%-tetrahydrocannabinol marijuana cigarette, a 2.5-mg dronabinol (delta-9-tetrahydrocannabinol) capsule, or a placebo capsule three times daily before meals.
HIV RNA levels, CD4+ and CD8+ cell subsets, and pharmacokinetic analyses of the protease inhibitors.
62 study participants were eligible for the primary end point (marijuana group, 20 patients; dronabinol group, 22 patients; and placebo group, 20 patients). Baseline HIV RNA level was less than 50 copies/mL for 36 participants (58%), and the median CD4+ cell count was 340 x 109 cells/L. When adjusted for baseline variables, the estimated average effect versus placebo on change in log10 viral load from baseline to day 21 was -0.07 (95% CI, -0.30 to 0.13) for marijuana and -0.04 (CI, -0.20 to 0.14) for dronabinol. The adjusted average changes in viral load in marijuana and dronabinol relative to placebo were -15% (CI, -50% to 34%) and -8% (CI, -37% to 37%), respectively. Neither CD4+ nor CD8+ cell counts appeared to be adversely affected by the cannabinoids.
Smoked and oral cannabinoids did not seem to be unsafe in people with HIV infection with respect to HIV RNA levels, CD4+ and CD8+ cell counts, or protease inhibitor levels over a 21-day treatment.
SARS-CoV-2 nucleocapsid antigen can be detected in plasma, but little is known about its performance as a diagnostic test for acute SARS-CoV-2 infection or infectious viral shedding among ...nonhospitalized individuals.
We used data generated from anterior nasal and blood samples collected in a longitudinal household cohort of SARS-CoV-2 cases and contacts. Participants were classified as true positives if polymerase chain reaction (PCR) positive for SARS-CoV-2 and as true negatives if PCR negative and seronegative. Infectious viral shedding was determined by the cytopathic effect from viral culture. Stratified by 7 days after symptom onset, we constructed receiver operating characteristic (ROC) curves to describe optimized accuracy (Youden index), optimized sensitivity, and specificity.
Of 80 participants, 58 (73%) were true positives while 22 (27%) were true negatives. Using the manufacturer's cutoff of 1.25 pg/mL for evaluating infection, sensitivity was higher from 0 to 7 days (77.6% 95% confidence interval {CI}, 64%-88.2%) than from 8 to 14 days (43.2% 95% CI, 31.1%-54.5%) after symptom onset; specificity was unchanged at 100% (95% CI, 88.1%-100%). This test had higher sensitivity (100% 95% CI, 88.4%-100%) and lower specificity (65% 95% CI, 40.8%-84.6%) for infectious viral shedding as compared with infection, particularly within the first week of symptom onset. Although the presence of N-antigen correlated with infectious viral shedding (
= 0.63;
< .01), sensitivity still declined over time. Additional cutoffs from ROC curves were identified to optimize sensitivity and specificity.
We found that this SARS-CoV-2 N-antigen test was highly sensitive for detecting early but not late infectious viral shedding, making it a viable screening test for community-dwelling individuals to inform isolation practices.
The central nervous system (CNS) is an important target of HIV, and cerebrospinal fluid (CSF) can provide a window into host-virus interactions within the CNS. The goal of this study was to determine ...whether HIV-specific CD8(+) T cells are present in CSF of HIV controllers (HC), who maintain low to undetectable plasma viremia without antiretroviral therapy (ART). CSF and blood were sampled from 11 HC, defined based on plasma viral load (VL) consistently below 2,000 copies/ml without ART. These included nine elite controllers (EC, plasma VL <40 copies/ml) and two viremic controllers (VC, VL 40-2,000 copies/ml). All controllers had CSF VL <40 copies/ml. Three comparison groups were also sampled: six HIV noncontrollers (NC, VL >10,000 copies/ml, no ART); seven individuals with viremia suppressed due to ART (Tx, VL <40 copies/ml); and nine HIV-negative controls. CD4(+) and CD8(+) T cells in CSF and blood were analyzed by flow cytometry to assess expression of CCR5, activation markers CD38 and HLA-DR, and memory/effector markers CD45RA and CCR7. HIV-specific CD8(+) T cells were quantified by major histocompatibility complex class I multimer staining. HIV-specific CD8(+) T cells were detected ex vivo at similar frequencies in CSF of HC and noncontrollers; the highest frequencies were in individuals with CD4 counts below 500 cells/μl. The majority of HIV-specific CD8(+) T cells in CSF were effector memory cells expressing CCR5. Detection of these cells in CSF suggests active surveillance of the CNS compartment by HIV-specific T cells, including in individuals with long-term control of HIV infection in the absence of therapy.
Twenty human immunodeficiency virus—infected patients experiencing virologic failure of an indinavir- or ritonavir-containing treatment regimen were evaluated in a prospective, open-label study. ...Subjects received nelfinavir, saquinavir, abacavir, and either another nucleoside analog (n = 10) or nevirapine (n = 10). Patients treated with the nevirapine-containing regimen experienced significantly greater virologic suppression at week 24 than those not treated with nevirapine (P = .04). Baseline phenotypic drug susceptibility was strongly correlated with outcome in both treatment arms. Subjects with baseline virus phenotypically sensitive to 2 or 3 drugs in the salvage regimen experienced significantly greater virus load suppression than those with baseline virus sensitive to 0 or 1 drug (median week-24 change = −2.24 log and −0.35 log, respectively; P = .01). In conclusion, non-nucleoside reverse transcriptase inhibitors may represent a potent drug in salvage therapy regimens after failure of an indinavir or ritonavir regimen. Phenotypic resistance testing may provide a useful tool for selecting more effective salvage regimens.
Abstract
We report a patient with connective tissue disease who developed modest severe acute respiratory syndrome coronavirus 2 receptor binding domain–specific antibody levels and a lack of ...neutralization capacity, despite having received 3 mRNA coronavirus disease 2019 vaccines and holding anti-B-cell therapy for >7 months before vaccination. The patient developed virus-specific T-cell responses.
HIV infection can result in depletion of total CD4(+) T cells and naive CD8(+) T cells, and in the generation of dysfunctional effector CD8(+) T cells. In this study, we show that naive CD8(+) T ...cells in subjects with progressive HIV disease express low levels of CD8α and CD8β chains. Such naive CD8(low) T cells display broad signaling defects across the T-cell receptor complex, and their appearance correlates with generalized up-regulation of major histocompatibility complex class I (MHC-I) antigens on peripheral blood mononuclear cells (PBMCs). To explore a causal link between increased MHC-I up-regulation and the generation of naive CD8(low) T cells, we used the humanized SCID-hu Thy/Liv mouse model to show that HIV infection of the thymus and interferon α (IFNα) treatment alone result in MHC-I up-regulation and in the generation of dysfunctional CD3(high)CD8(+)CD4(-) single-positive 8 (SP8) thymocytes with low expression of CD8. We suggest that dysfunctional naive CD8(low) T cells are generated as a result of IFNα-mediated up-regulation of MHC-I on stromal cells in the thymus and antigen-presenting cells in the periphery, and that dysfunction in this naive compartment contributes to the immunodeficiency of HIV disease. This study is registered at www.clinicaltrials.gov as NCT00187512.
HIV “controllers” are persons infected with human immunodeficiency virus, type I (HIV) who maintain long-term control of viremia without antiviral therapy and who usually do not develop the acquired ...immune deficiency syndrome (AIDS). In this study, we have correlated results from polychromatic flow cytometry and oligonucleotide expression arrays to characterize the mucosal immune responses of these subjects in relation to untreated HIV+ persons with high viral loads and progressive disease (“noncontrollers”). Paired peripheral blood and rectosigmoid biopsies were analyzed from 9 controllers and 11 noncontrollers. Several cellular immune parameters were found to be concordant between the 2 compartments. Compared with noncontrollers, the mucosal tissues of controllers had similar levels of effector T cells and fewer regulatory T cells (Tregs). Using principal component analysis to correlate immunologic parameters with gene expression profiles, transcripts were identified that accurately distinguished between controllers and noncontrollers. Direct 2-way comparison also revealed genes that are significantly different in their expression between controllers and noncontrollers, all of which had reduced expression in controllers. In addition to providing an approach that integrates flow cytometry datasets with transcriptional profiling analysis, these results underscore the importance of the sustained inflammatory response that attends progressive HIV disease.
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