Abstract
High-throughput molecular testing for severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) may be enabled by group testing in which pools of specimens are screened, and individual ...specimens tested only after a pool tests positive. Several laboratories have recently published examples of pooling strategies applied to SARS-CoV-2 specimens, but overall guidance on efficient pooling strategies is lacking. Therefore we developed a model of the efficiency and accuracy of specimen pooling algorithms based on available data on SAR-CoV-2 viral dynamics. For a fixed number of tests, we estimate that programs using group testing could screen 2–20 times as many specimens compared with individual testing, increase the total number of true positive infections identified, and improve the positive predictive value of results. We compare outcomes that may be expected in different testing situations and provide general recommendations for group testing implementation. A free, publicly-available Web calculator is provided to help inform laboratory decisions on SARS-CoV-2 pooling algorithms.
High-throughput molecular testing for severe acute respiratory syndrome–coronavirus 2 may be enabled by group testing. Group versus individual testing could allow screening of 2–20 times as many specimens per test and increase the positive predictive value of results.
Several human APOBEC3 deaminases can inhibit HIV-1 replication in vitro. HIV-1 Vif counteracts this restriction by targeting APOBEC3 for proteasomal degradation. Human APOBEC3H (A3H) is highly ...polymorphic, with natural variants differing considerably in anti-HIV-1 activity in vitro. To examine HIV-1 adaptation to variation in A3H activity in a natural infection context, we determined the A3H haplotypes and Vif sequences from 76 recently infected HIV-1 patients. We detected A3H-specific Vif changes suggesting viral adaptation. The patient-derived Vif sequences were used to engineer viruses that specifically differed in their ability to counteract A3H. Replication of these Vif-variant viruses in primary T cells naturally expressing active or inactive A3H haplotypes showed that endogenously expressed A3H restricts HIV-1 replication. Proviral DNA from A3H-restricted viruses showed high levels of G-to-A mutations in an A3H-specific GA dinucleotide context. Taken together, our data validate A3H expressed at endogenous levels as a bona fide HIV-1 restriction factor.
•Patients with active A3H more often have an A3H-resistant HIV•Endogenously expressed A3H restricts HIV replication in primary cells•A3H restriction of HIV in primary cells correlates with proviral editing•The Vif amino acid at position 39 determines degradation efficiency of A3H
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Although efficacy is unknown, many men who have sex with men (MSM) attempt to reduce HIV risk by adapting condom use, partner selection, or sexual position to the partner's HIV serostatus. We ...assessed the association of seroadaptive practices with HIV acquisition.
We pooled data on North American MSM from four longitudinal HIV-prevention studies. Sexual behaviors reported during each six-month interval were assigned sequentially to one of six mutually exclusive risk categories: (1) no unprotected anal intercourse (UAI), (2) having a single negative partner, (3) being an exclusive top (only insertive anal sex), (4) serosorting (multiple partners, all HIV negative), (5) seropositioning (only insertive anal sex with potentially discordant partners), and (6) UAI with no seroadaptive practices. HIV antibody testing was conducted at the end of each interval. We used Cox models to evaluate the independent association of each category with HIV acquisition, controlling for number of partners, age, race, drug use, and intervention assignment. 12,277 participants contributed to 60,162 six-month intervals with 663 HIV seroconversions. No UAI was reported in 47.4% of intervals, UAI with some seroadaptive practices in 31.8%, and UAI with no seroadaptive practices in 20.4%. All seroadaptive practices were associated with a lower risk, compared to UAI with no seroadaptive practices. However, compared to no UAI, serosorting carried twice the risk (HR = 2.03, 95%CI:1.51-2.73), whereas seropositioning was similar in risk (HR = 0.85, 95%CI:0.50-1.44), and UAI with a single negative partner and as an exclusive top were both associated with a lower risk (HR = 0.56, 95%CI:0.32-0.96 and HR = 0.55, 95%CI:0.36-0.84, respectively).
Seroadaptive practices appear protective when compared with UAI with no seroadaptive practices, but serosorting appears to be twice as risky as no UAI. Condom use and limiting number of partners should be advocated as first-line prevention strategies, but seroadaptive practices may be considered harm-reduction for men at greatest risk.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background. We examined whether viral dynamics in the genital tract during the natural history of acute human immunodeficiency virus type 1 (HIV-1) infection could explain efficient heterosexual ...transmission of HIV. Methods. We measured HIV-1 concentration in blood and semen samples from patients with acute and long-term HIV-1 infection. We explored the effect of changes in viral dynamics in semen on the probability of transmission per coital act, using a probabilistic model published elsewhere. Results. Considered over time from infection, semen HIV-1 concentrations, in men with acute infection, increase and decrease in approximate parallel with changes occurring in blood. Modeling suggests that these acute dynamics alone are sufficient to increase probability of heterosexual transmission by 8–10-fold between peak (day 20 after infection, based on the model) and virologic set points (day 54 and later after infection). Depending on the frequency of coitus, men with average semen HIV-1 loads and without sexually transmitted diseases (STDs) would be expected to infect 7%–24% of susceptible female sex partners during the first 2 months of infection. The predicted infection rate would be much higher when either partner has an STD. Conclusions. Empirical biological data strongly support the hypothesis that sexual transmission by acutely infected individuals has a disproportionate effect on the spread of HIV-1 infection. Acute hyperinfectiousness may, in part, explain the current pandemic in heterosexual individuals.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
BACKGROUND:Antiretroviral therapy (ART) is typically begun weeks after HIV diagnosis. We assessed the acceptability, feasibility, safety, and efficacy of initiating ART on the same day as diagnosis.
...METHODS:We studied a clinic-based cohort consisting of consecutive patients who were referred with new HIV diagnosis between June 2013 and December 2014. A subset of patients with acute or recent infection (<6 months) or CD4 <200 were managed according to a “RAPID” care initiation protocol. An intensive, same-day appointment included social needs assessment; medical provider evaluation; and a first ART dose offered after laboratories were drawn. Patient acceptance of ART, drug toxicities, drug resistance, and time to viral suppression outcomes were compared between RAPID participants and contemporaneous patients (who were not offered the program), and with an historical cohort.
RESULTS:Among 86 patients, 39 were eligible and managed on the RAPID protocol. Thirty-seven (94.9%) of 39 in RAPID began ART within 24 hours. Minor toxicity with the initial regimen occurred in 2 (5.1%) of intervention patients versus none in the nonintervention group. Loss to follow-up was similar in intervention (10.3%) and nonintervention patients (14.9%) during the study. Time to virologic suppression (<200 copies HIV RNA/mL) was significantly faster (median 1.8 months) among intervention-managed patients when compared with patients treated in the same clinic under prior recommendations for universal ART (4.3 months; P = 0.0001).
CONCLUSIONS:Treatment for HIV infection can be started on the day of diagnosis without impacting the safety or acceptability of ART. Same-day ART may shorten the time to virologic suppression.
Background. CD4⁺/CD8⁺ T-cell activation levels often remain elevated in chronic human immunodeficiency virus (HIV) infection despite initiation of antiretroviral therapy (ART). T-cell activation ...predicts early death and blunted CD4⁺ T-cell recovery during ART and may affect persistent HIV reservoir size. We investigated whether very early ART initiation is associated with lower on-therapy immune activation and HIV persistence. Methods. From a cohort of patients with early HIV infection (<6 months duration since infection) we identified persons who started ART early (< 6 months after infection) or later (≥2 years after infection) and maintained ≥2 years of virologie suppression; at-risk HIV-negative persons were controls. We measured CD4⁺/CD8⁺ T-cell activation (percent CD38⁺/HLA-DR⁻) and HIV reservoir size (based on HIV DNA and cell-associated RNA levels). Results. In unadjusted analyses, early ART predicted lower on-therapy CD8⁺ T-cell activation (n = 34; mean, 22.1%) than achieved with later ART (n = 32; mean, 28.8%; P = .009), although levels in early ART remained elevated relative to HIV-negative controls (P = .02). Early ART also predicted lower CD4⁺ T-cell activation than with later ART (5.3% vs 7.5%; P = .06). Early ART predicted 4.8-fold lower DNA levels than achieved with later ART (P = .005), and lower cell-associated RNA levels (difference in signal-to-cutoff ratio (S/Co), 3.2; P = .035). Conclusions. ART initiation <6 months after infection is associated with lower levels of T-cell activation and smaller HIV DNA and RNA reservoir size during long-term therapy.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Introduction: The unchanged global HIV incidence may be related to ignoring acute HIV infection (AHI). This scoping review examines diagnostic, clinical, and public health implications of identifying ...and treating persons with AHI.
Methods: We searched PubMed, in addition to hand‐review of key journals identifying research pertaining to AHI detection and treatment. We focused on the relative contribution of AHI to transmission and the diagnostic, clinical, and public health implications. We prioritized research from low‐ and middle‐income countries (LMICs) published in the last fifteen years.
Results and Discussion: Extensive AHI research and limited routine AHI detection and treatment have begun in LMIC. Diagnostic challenges include ease‐of‐use, suitability for application and distribution in LMIC, and throughput for high‐volume testing. Risk score algorithms have been used in LMIC to screen for AHI among individuals with behavioural and clinical characteristics more often associated with AHI. However, algorithms have not been implemented outside research settings. From a clinical perspective, there are substantial immunological and virological benefits to identifying and treating persons with AHI – evading the irreversible damage to host immune systems and seeding of viral reservoirs that occurs during untreated acute infection. The therapeutic benefits require rapid initiation of antiretrovirals, a logistical challenge in the absence of point‐of‐care testing. From a public health perspective, AHI diagnosis and treatment is critical to: decrease transmission via viral load reduction and behavioural interventions; improve pre‐exposure prophylaxis outcomes by avoiding treatment initiation for HIV‐seronegative persons with AHI; and, enhance partner services via notification for persons recently exposed or likely transmitting.
Conclusions: There are undeniable clinical and public health benefits to AHI detection and treatment, but also substantial diagnostic and logistical barriers to implementation and scale‐up. Effective early ART initiation may be critical for HIV eradication efforts, but widespread use in LMIC requires simple and accurate diagnostic tools. Implementation research is critical to facilitate sustainable integration of AHI detection and treatment into existing health systems and will be essential for prospective evaluation of testing algorithms, point‐of‐care diagnostics, and efficacious and effective first‐line regimens.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Gut microbes can profoundly modulate mucosal barrier-promoting Th17 cells in mammals. A salient feature of HIV/simian immunodeficiency virus (SIV) immunopathogenesis is the loss of Th17 cells, which ...has been linked to increased activity of the immunomodulatory enzyme, indoleamine 2,3-dioxygenase 1 (IDO 1). The role of gut microbes in this system remains unknown, and the SIV-infected rhesus macaque provides a well-described model for HIV-associated Th17 loss and mucosal immune disruption. We observed a specific depletion of gut-resident Lactobacillus during acute and chronic SIV infection of rhesus macaques, which was also seen in early HIV-infected humans. This depletion in rhesus macaques correlated with increased IDO1 activity and Th17 loss. Macaques supplemented with a Lactobacillus-containing probiotic exhibited decreased IDO1 activity during chronic SIV infection. We propose that Lactobacillus species inhibit mammalian IDO1 and thus may help to preserve Th17 cells during pathogenic SIV infection, providing support for Lactobacillus species as modulators of mucosal immune homeostasis.
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•IDO1 activity correlates with loss of barrier-promoting Th17 cells in SIV infection•Abundance of gut-resident Lactobacillus correlates with IDO1 activity and Th17 cells•Probiotics containing Lactobacillus reduce IDO1 activity in SIV-infected macaques
Vujkovic-Cvijin et al. show that fecal Lactobacillus associates with control of the immunomodulatory indoleamine 2,3-dioxygenase (IDO) pathway, providing a link between the gut microbiome and mucosal immune homeostasis in the pathogenesis of SIV disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Current laboratory and point-of-care tests for HIV detect different analytes and use different sample types. Some have fast turnaround times (<1 hour). We investigated how HIV test choice could ...impact case finding by testing programs.
We analyzed 21,234 consecutive HIV tests with venous blood obtained by San Francisco HIV testing programs from 2003 to 2008. For a subset, oral fluid (n = 6446) or fingerstick blood (n = 8127) samples were also obtained for rapid testing. In all cases, HIV status was determined using an HIV antibody-plus-RNA test algorithm. We assessed how the screening antibody tests performed individually versus the gold standard of the full algorithm. We then evaluated the potential ability of other tests (including new tests) to detect more cases, by re-testing all specimens that had negative/discrepant antibody results on initial screening.
The antibody-RNA algorithm identified 58 acute and 703 established HIV infection cases. 1(st)-generation (Vironostika) and 3(rd)-generation (Genetic Systems) immunoassays had 92 and 96 percent sensitivity, respectively. The Oraquick rapid test had clinical sensitivity of only 86 percent on oral fluid samples, but 92 percent on finger-stick blood. Newer 4(th)-generation, antigen-antibody combo rapid immunoassay (ARCHITECT) detected HIV in 87 percent of all the acute cases that had been missed by one of the previous screening assays. A point-of-care 4(th) generation antigen-antibody combo rapid test (Determine) detected about 54 percent of such acute cases.
Our study suggests that some rapid antibody blood tests will give similar case detection to laboratory antibody tests, but that oral fluid testing greatly reduces ability to detect HIV. New 4(th)-generation combo tests can detect the majority of acute infections detectable by HIV RNA but with rapid results. Using these tests as a primary screening assay in high-risk HIV testing programs could reduce or eliminate the need for HIV RNA testing.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Rapid diagnostic tests that might be capable of detecting human immunodeficiency virus (HIV) antigens or nucleic acids represent the possibility of merging 2 key advancements in HIV testing: rapid ...testing and detection of acute HIV infection. In this article, we review the public health goals of rapid HIV testing and acute HIV testing and explore how rapid tests to directly detect HIV antigens or nucleic acids might alter current approaches to HIV case identification in clinical and public health screening settings. We discuss the specific types of HIV screening programs and settings in which direct viral rapid testing would offer an important advantage. Finally, we suggest priorities in operations research that must be achieved to pave the way for the future introduction of direct rapid viral testing technologies in the HIV testing marketplace.
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