Changes to inflammatory markers during 5 years of viral suppression and during viral blips in people with HIV initiating different integrase inhibitor based regimens.
Heightened levels of inflammatory markers are linked to increased morbidity/mortality in people with HIV (PWH) and often remain elevated after virologic suppression by antiretroviral therapy (ART). As new combinations of ART become available, an evaluation of their effects on immune activation and inflammation is warranted. Additionally, it remains unknown whether transient increases in viral load ("blips") during ART are associated with increases in inflammation.
We utilized cryopreserved samples from treatment-naïve PWH enrolled in two Phase 3 clinical trials investigating the efficacy and safety of bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) or dolutegravir, abacavir, and lamivudine (DTG/ABC/3TC) or DTG + F/TAF over a 5-year window (GS-US-380-1489/1490). At week 144, participants were offered the option to switch to open label B/F/TAF for an additional 96 weeks. We measured levels of interleukin-6 (IL-6), C-reactive protein (hsCRP), D-dimer, soluble CD14 (sCD14), and tumor necrosis factor-α receptor 1 (TNFR1) from available baseline, week 24, 48, 144, and 240 samples (B/F/TAF, N=123; DTG/ABC/3TC, N=62; DTG+F/TAF, N=58). Additional samples from PWH who experienced a viral blip (n=44, defined as a single HIV-1 RNA >50c/mL) were also analyzed and paired with the most recent available suppressed sample before the blip. Longitudinal biomarker changes were assessed using a constrained mixed effects linear regression model adjusting for covariates.
Baseline demographics and selected laboratory characteristics were similar across groups. Levels of D-dimer, sCD14, and TNFR1 decreased significantly from baseline in all treatment arms, with no significant differences between arms at any timepoint. Biomarker levels also remained stable following ART-switch at week 144. No significant changes in hsCRP or IL-6 were observed versus baseline in any arm at any timepoint. A significant association was observed between sCD14 and increasing viral load (p=0.022) in viral blips; D-dimer also increased with blips in the B/F/TAF arm.
Viral suppression was associated with reductions in most inflammatory markers in PWH, with no significant differences among the three ART regimens during the 144-week randomized period. These decreases were sustained after the open label switch to B/F/TAF. Viral blips were associated with increases in monocyte activation (sCD14). Further analysis is needed to confirm these findings and determine the potential impact on clinical outcomes.
Funderburg NT
，Huang SSY
，Cohen C
，Ailstock K
，Cummings M
，Lee JC
，Ng B
，White K
，Wallin JJ
，Downie B
，McComsey GA
... -
《Frontiers in Immunology》
The effect of sample site and collection procedure on identification of SARS-CoV-2 infection.
Sample collection is a key driver of accuracy in the diagnosis of SARS-CoV-2 infection. Viral load may vary at different anatomical sampling sites and accuracy may be compromised by difficulties obtaining specimens and the expertise of the person taking the sample. It is important to optimise sampling accuracy within cost, safety and accessibility constraints.
To compare the sensitivity of different sampling collection sites and methods for the detection of current SARS-CoV-2 infection with any molecular or antigen-based test.
Electronic searches of the Cochrane COVID-19 Study Register and the COVID-19 Living Evidence Database from the University of Bern (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) were undertaken on 22 February 2022. We included independent evaluations from national reference laboratories, FIND and the Diagnostics Global Health website. We did not apply language restrictions.
We included studies of symptomatic or asymptomatic people with suspected SARS-CoV-2 infection undergoing testing. We included studies of any design that compared results from different sample types (anatomical location, operator, collection device) collected from the same participant within a 24-hour period.
Within a sample pair, we defined a reference sample and an index sample collected from the same participant within the same clinical encounter (within 24 hours). Where the sample comparison was different anatomical sites, the reference standard was defined as a nasopharyngeal or combined naso/oropharyngeal sample collected into the same sample container and the index sample as the alternative anatomical site. Where the sample comparison was concerned with differences in the sample collection method from the same site, we defined the reference sample as that closest to standard practice for that sample type. Where the sample pair comparison was concerned with differences in personnel collecting the sample, the more skilled or experienced operator was considered the reference sample. Two review authors independently assessed the risk of bias and applicability concerns using the QUADAS-2 and QUADAS-C checklists, tailored to this review. We present estimates of the difference in the sensitivity (reference sample (%) minus index sample sensitivity (%)) in a pair and as an average across studies for each index sampling method using forest plots and tables. We examined heterogeneity between studies according to population (age, symptom status) and index sample (time post-symptom onset, operator expertise, use of transport medium) characteristics.
This review includes 106 studies reporting 154 evaluations and 60,523 sample pair comparisons, of which 11,045 had SARS-CoV-2 infection. Ninety evaluations were of saliva samples, 37 nasal, seven oropharyngeal, six gargle, six oral and four combined nasal/oropharyngeal samples. Four evaluations were of the effect of operator expertise on the accuracy of three different sample types. The majority of included evaluations (146) used molecular tests, of which 140 used RT-PCR (reverse transcription polymerase chain reaction). Eight evaluations were of nasal samples used with Ag-RDTs (rapid antigen tests). The majority of studies were conducted in Europe (35/106, 33%) or the USA (27%) and conducted in dedicated COVID-19 testing clinics or in ambulatory hospital settings (53%). Targeted screening or contact tracing accounted for only 4% of evaluations. Where reported, the majority of evaluations were of adults (91/154, 59%), 28 (18%) were in mixed populations with only seven (4%) in children. The median prevalence of confirmed SARS-CoV-2 was 23% (interquartile (IQR) 13%-40%). Risk of bias and applicability assessment were hampered by poor reporting in 77% and 65% of included studies, respectively. Risk of bias was low across all domains in only 3% of evaluations due to inappropriate inclusion or exclusion criteria, unclear recruitment, lack of blinding, nonrandomised sampling order or differences in testing kit within a sample pair. Sixty-eight percent of evaluation cohorts were judged as being at high or unclear applicability concern either due to inflation of the prevalence of SARS-CoV-2 infection in study populations by selectively including individuals with confirmed PCR-positive samples or because there was insufficient detail to allow replication of sample collection. When used with RT-PCR • There was no evidence of a difference in sensitivity between gargle and nasopharyngeal samples (on average -1 percentage points, 95% CI -5 to +2, based on 6 evaluations, 2138 sample pairs, of which 389 had SARS-CoV-2). • There was no evidence of a difference in sensitivity between saliva collection from the deep throat and nasopharyngeal samples (on average +10 percentage points, 95% CI -1 to +21, based on 2192 sample pairs, of which 730 had SARS-CoV-2). • There was evidence that saliva collection using spitting, drooling or salivating was on average -12 percentage points less sensitive (95% CI -16 to -8, based on 27,253 sample pairs, of which 4636 had SARS-CoV-2) compared to nasopharyngeal samples. We did not find any evidence of a difference in the sensitivity of saliva collected using spitting, drooling or salivating (sensitivity difference: range from -13 percentage points (spit) to -21 percentage points (salivate)). • Nasal samples (anterior and mid-turbinate collection combined) were, on average, 12 percentage points less sensitive compared to nasopharyngeal samples (95% CI -17 to -7), based on 9291 sample pairs, of which 1485 had SARS-CoV-2. We did not find any evidence of a difference in sensitivity between nasal samples collected from the mid-turbinates (3942 sample pairs) or from the anterior nares (8272 sample pairs). • There was evidence that oropharyngeal samples were, on average, 17 percentage points less sensitive than nasopharyngeal samples (95% CI -29 to -5), based on seven evaluations, 2522 sample pairs, of which 511 had SARS-CoV-2. A much smaller volume of evidence was available for combined nasal/oropharyngeal samples and oral samples. Age, symptom status and use of transport media do not appear to affect the sensitivity of saliva samples and nasal samples. When used with Ag-RDTs • There was no evidence of a difference in sensitivity between nasal samples compared to nasopharyngeal samples (sensitivity, on average, 0 percentage points -0.2 to +0.2, based on 3688 sample pairs, of which 535 had SARS-CoV-2).
When used with RT-PCR, there is no evidence for a difference in sensitivity of self-collected gargle or deep-throat saliva samples compared to nasopharyngeal samples collected by healthcare workers when used with RT-PCR. Use of these alternative, self-collected sample types has the potential to reduce cost and discomfort and improve the safety of sampling by reducing risk of transmission from aerosol spread which occurs as a result of coughing and gagging during the nasopharyngeal or oropharyngeal sample collection procedure. This may, in turn, improve access to and uptake of testing. Other types of saliva, nasal, oral and oropharyngeal samples are, on average, less sensitive compared to healthcare worker-collected nasopharyngeal samples, and it is unlikely that sensitivities of this magnitude would be acceptable for confirmation of SARS-CoV-2 infection with RT-PCR. When used with Ag-RDTs, there is no evidence of a difference in sensitivity between nasal samples and healthcare worker-collected nasopharyngeal samples for detecting SARS-CoV-2. The implications of this for self-testing are unclear as evaluations did not report whether nasal samples were self-collected or collected by healthcare workers. Further research is needed in asymptomatic individuals, children and in Ag-RDTs, and to investigate the effect of operator expertise on accuracy. Quality assessment of the evidence base underpinning these conclusions was restricted by poor reporting. There is a need for further high-quality studies, adhering to reporting standards for test accuracy studies.
Davenport C
，Arevalo-Rodriguez I
，Mateos-Haro M
，Berhane S
，Dinnes J
，Spijker R
，Buitrago-Garcia D
，Ciapponi A
，Takwoingi Y
，Deeks JJ
，Emperador D
，Leeflang MMG
，Van den Bruel A
，Cochrane COVID-19 Diagnostic Test Accuracy Group
... -
《Cochrane Database of Systematic Reviews》
ResearchGate
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