A pseudoknot forms in an RNA when nucleotides in a loop pair with a region outside the helices that close the loop. Pseudoknots occur relatively rarely in RNA but are highly overrepresented in ...functionally critical motifs in large catalytic RNAs, in riboswitches, and in regulatory elements of viruses. Pseudoknots are usually excluded from RNA structure prediction algorithms. When included, these pairings are difficult to model accurately, especially in large RNAs, because allowing this structure dramatically increases the number of possible incorrect folds and because it is difficult to search the fold space for an optimal structure. We have developed a concise secondary structure modeling approach that combines SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension) experimental chemical probing information and a simple, but robust, energy model for the entropie cost of single pseudoknot formation. Structures are predicted with iterative refinement, using a dynamic programming algorithm. This melded experimental and thermodynamic energy function predicted the secondary structures and the pseudoknots for a set of 21 challenging RNAs of known structure ranging in size from 34 to 530 nt. On average, 93% of known base pairs were predicted, and all pseudoknots in well-folded RNAs were identified.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The HIV care continuum (diagnosis, linkage to care, retention in care, receipt of antiretroviral therapy (ART), viral suppression) has been used to identify opportunities for improving the delivery ...of HIV care. Continuum steps are typically calculated in a conditional manner, with the number of persons completing the prior step serving as the base population for the next step. This approach may underestimate the prevalence of viral suppression by excluding patients who are suppressed but do not meet standard definitions of retention in care. Understanding how retention in care and viral suppression interact and change over time may improve our ability to intervene on these steps in the continuum.
We followed 17,140 patients at 11 U.S. HIV clinics between 2010-2012. For each calendar year, patients were classified into one of five categories: (1) retained/suppressed, (2) retained/not-suppressed, (3) not-retained/suppressed, (4) not-retained/not-suppressed, and (5) lost to follow-up (for calendar years 2011 and 2012 only). Retained individuals were those completing ≥ 2 HIV medical visits separated by ≥ 90 days in the year. Persons not retained completed ≥ 1 HIV medical visit during the year, but did not meet the retention definition. Persons lost to follow-up had no HIV medical visits in the year. HIV viral suppression was defined as HIV-1 RNA ≤ 200 copies/mL at the last measure in the year. Multinomial logistic regression was used to determine the probability of patients' transitioning between retention/suppression categories from 2010 to 2011 and 2010 to 2012, adjusting for age, sex, race/ethnicity, HIV risk factor, insurance status, CD4 count, and use of ART.
Overall, 65.8% of patients were retained/suppressed, 17.4% retained/not-suppressed, 10.0% not-retained/suppressed, and 6.8% not-retained/not-suppressed in 2010. 59.5% of patients maintained the same status in 2011 (kappa=0.458) and 53.3% maintained the same status in 2012 (kappa=0.437).
Not counting patients not-retained/suppressed as virally suppressed, as is commonly done in the HIV care continuum, underestimated the proportion suppressed by 13%. Applying the care continuum in a longitudinal manner will enhance its utility.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Prior efforts to estimate U.S. prevalence of substance use disorders (SUDs) in HIV care have been undermined by caveats common to single-site trials. The current work reports on a cohort of 10,652 ...HIV-positive adults linked to care at seven sites, with available patient data including geography, demography, and risk factor indices, and with substance-specific SUDs identified via self-report instruments with validated diagnostic thresholds. Generalized estimating equations also tested patient indices as SUD predictors. Findings were: (1) a 48 % SUD prevalence rate (between-site range of 21–71 %), with 20 % of the sample evidencing polysubstance use disorder; (2) substance-specific SUD rates of 31 % for marijuana, 19 % alcohol, 13 % methamphetamine, 11 % cocaine, and 4 % opiate; and (3) emergence of younger age and male gender as robust SUD predictors. Findings suggest high rates at which SUDs occur among patients at these urban HIV care sites, detail substance-specific SUD rates, and identify at-risk patient subgroups.
BACKGROUND:The clinical management of low-level viremia (LLV) remains unclear. The objective of this study was to investigate the association of blips and LLV with virologic failure.
METHODS:We ...enlisted patients who newly enrolled into the HIV Research Network between 2005 and 2015, had HIV-1 RNA more than 200 copies/ml, and were either antiretroviral therapy (ART)-naive or ART-experienced and not on ART. Patients were included who achieved virologic suppression (≤50 on two consecutive viral loads) and had at least two viral loads following suppression. Blips and LLV (≥2 consecutive >51 copies/ml) were categorized separately into three categoriesno blips/LLV, 51–200, 201–500. Cox proportional hazards regression was used to assess association between rates of blips/LLV and virologic failure (two consecutive >500).
RESULTS:The 2795 patients were mostly male (75.4%), black (50.3%), and MSM (52.9%). Median age was 38 years old (interquartile range 29–48). Most patients (88.8%) were ART-naive at study entry. Overall, 283 (10.1%) patients experienced virologic failure. A total of 152 (5.4%) patients experienced LLV to 51–200 and 110 (3.9%) patients experienced LLV to 201–500. Both LLV 51–200 adjusted hazard ratio (aHR) 1.83 (1.10,3.04) and LLV 201–500 aHR 4.26 (2.65,6.86) were associated with virologic failure. In sensitivity analysis excluding ART-experienced patients, the association between LLV 51 and 200 and virologic failure was not statistically significant.
CONCLUSION:LLV between 201 and 500 was associated with virologic failure, as was LLV between 51 and 200, particularly among ART-experienced patients. Patients with LLV below the current Department of Health and Human Services threshold for virologic failure (persistent viremia ≥200) may require more intensive monitoring because of increased risk for virologic failure.
Hazardous alcohol use is associated with detrimental health outcomes among persons living with HIV (PLWH). We examined the prevalence and factors associated with hazardous alcohol use in the current ...era using several hazardous drinking definitions and binge drinking defined as ≥5 drinks for men versus ≥4 for women. We included 8567 PLWH from 7 U.S. sites from 2013 to 2015. Current hazardous alcohol use was reported by 27% and 34% reported binge drinking. In adjusted analyses, current and past cocaine/crack (odd ratio OR 4.1:3.3–5.1, p < 0.001 and OR 1.3:1.1–1.5, p < 0.001 respectively), marijuana (OR 2.5:2.2–2.9, p < 0.001 and OR 1.4:1.2–1.6, p < 0.001), and cigarette use (OR 1.4:1.2–1.6, p < 0.001 and OR 1.3:1.2–1.5, p < 0.001) were associated with increased hazardous alcohol use. The prevalence of hazardous alcohol use remains high in the current era, particularly among younger men. Routine screening and targeted interventions for hazardous alcohol use, potentially bundled with interventions for other drugs, remain a key aspect of HIV care.
Because HIV viral suppression is essential for optimal outcomes and prevention efforts, understanding trends and predictors is imperative to inform public health policy.
To evaluate viral suppression ...trends in people living with HIV (PLWH), including the relationship of associated factors, such as demographic characteristics and integrase strand transfer inhibitor (ISTI) use.
Longitudinal observational cohort study.
8 HIV clinics across the United States.
PLWH receiving clinical care.
To understand trends in viral suppression (≤400 copies/mL), annual viral suppression rates from 1997 to 2015 were determined. Analyses were repeated with tests limited to 1 random test per person per year and using inverse probability of censoring weights to address loss to follow-up. Joint longitudinal and survival models and linear mixed models of PLWH receiving antiretroviral therapy (ART) were used to examine associations between viral suppression or continuous viral load (VL) levels and demographic factors, substance use, adherence, and ISTI use.
Viral suppression increased from 32% in 1997 to 86% in 2015 on the basis of all tests among 31 930 PLWH. In adjusted analyses, being older (odds ratio OR, 0.76 per decade 95% CI, 0.74 to 0.78) and using an ISTI-based regimen (OR, 0.54 CI, 0.51 to 0.57) were associated with lower odds of having a detectable VL, and black race was associated with higher odds (OR, 1.68 CI, 1.57 to 1.80) (P < 0.001 for each). Similar patterns were seen with continuous VL levels; when analyses were limited to 2010 to 2015; and with adjustment for adherence, substance use, or depression.
Results are limited to PLWH receiving clinical care.
HIV viral suppression rates have improved dramatically across the United States, which is likely partially attributable to improved ART, including ISTI-based regimens. However, disparities among younger and black PLWH merit attention.
National Institutes of Health.
Abstract
Background
Independent of CD4 cell count, a low CD4/CD8 ratio in people with HIV (PWH) is associated with deleterious immune senescence, activation, and inflammation, which may contribute to ...carcinogenesis and excess cancer risk. We examined whether low CD4/CD8 ratios predicted cancer among PWH in the United States and Canada.
Methods
We examined all cancer-free PWH with 1 or more CD4/CD8 values from North American AIDS Cohort Collaboration on Research and Design observational cohorts with validated cancer diagnoses between 1998 and 2016. We evaluated the association between time-lagged CD4/CD8 ratio and risk of specific cancers in multivariable, time-updated Cox proportional hazard models using restricted cubic spines. Models were adjusted for age, sex, race and ethnicity, hepatitis C virus, and time-updated CD4 cell count, HIV RNA, and history of AIDS-defining illness.
Results
Among 83 893 PWH, there were 5628 incident cancers, including lung cancer (n = 755), Kaposi sarcoma (n = 501), non-Hodgkin lymphoma (n = 497), and anal cancer (n = 439). The median age at cohort entry was 43 years. The overall median 6-month lagged CD4/CD8 ratio was 0.52 (interquartile range = 0.30-0.82). Compared with a 6-month lagged CD4/CD8 of 0.80, a CD4/CD8 of 0.30 was associated with increased risk of any incident cancer (adjusted hazard ratio = 1.24 95% confidence interval = 1.14 to 1.35). The CD4/CD8 ratio was also inversely associated with non-Hodgkin lymphoma, Kaposi sarcoma, lung cancer, anal cancer, and colorectal cancer in adjusted analyses (all 2-sided P < .05). Results were similar using 12-, 18-, and 24-month lagged CD4/CD8 values.
Conclusions
A low CD4/CD8 ratio up to 24 months before cancer diagnosis was independently associated with increased cancer risk in PWH and may serve as a clinical biomarker.
Depressive symptoms vary in severity and chronicity. We used group-based trajectory models to describe trajectories of depressive symptoms (measured using the Patient Health Questionnaire-9) and ...predictors of trajectory group membership among 1493 HIV-infected men (84%) and 292 HIV-infected women (16%). At baseline, 29% of women and 26% of men had depressive symptoms. Over a median of 30 months of follow-up, we identified four depressive symptom trajectories for women (labeled “low” experienced by 56% of women, “mild/moderate” 24%, “improving” 14%, and “severe” 6%) and five for men (“low” 61%, “mild/moderate” 14%, “rebounding” 5%, “improving” 13%, and “severe” 7%). Baseline antidepressant prescription, panic symptoms, and prior mental health diagnoses were associated with more severe or dynamic depressive symptom trajectories. Nearly a quarter of participants experienced some depressive symptoms, highlighting the need for improved depression management. Addressing more severe or dynamic depressive symptom trajectories may require interventions that additionally address mental health comorbidities.
Understanding advances in the care and treatment of adults with HIV as well as remaining gaps requires comparing differences in mortality between persons entering care for HIV and the general ...population.
To assess the extent to which mortality among persons entering HIV care in the United States is elevated over mortality among matched persons in the general U.S. population and trends in this difference over time.
Observational cohort study.
Thirteen sites from the U.S. North American AIDS Cohort Collaboration on Research and Design.
82 766 adults entering HIV clinical care between 1999 and 2017 and a subset of the U.S. population matched on calendar time, age, sex, race/ethnicity, and county using U.S. mortality and population data compiled by the National Center for Health Statistics.
Five-year all-cause mortality, estimated using the Kaplan-Meier estimator of the survival function.
Overall 5-year mortality among persons entering HIV care was 10.6%, and mortality among the matched U.S. population was 2.9%, for a difference of 7.7 (95% CI, 7.4 to 7.9) percentage points. This difference decreased over time, from 11.1 percentage points among those entering care between 1999 and 2004 to 2.7 percentage points among those entering care between 2011 and 2017.
Matching on available covariates may have failed to account for differences in mortality that were due to sociodemographic factors rather than consequences of HIV infection and other modifiable factors.
Mortality among persons entering HIV care decreased dramatically between 1999 and 2017, although those entering care remained at modestly higher risk for death in the years after starting care than comparable persons in the general U.S. population.
National Institutes of Health.
People living with HIV (PWH) are experiencing an increased prevalence of non-AIDS-defining cancers (NADCs). Our study investigated the association of immunosuppression and HIV control with NADCs ...among PWH on antiretroviral therapy (ART) in the United States.
Among patients across 8 clinical cohorts on ART between 1996 and 2016, we assessed immune function and HIV control using 3 parameterizations of CD4 count and HIV-RNA viral load (VL): (1) CD4 or VL at ART initiation; (2) change in CD4 or VL after ART initiation; and (3) proportion of follow-up time at CD4 >500 cells/µL or VL <50 copies/mL. Cox models were used to ascertain the association of these measures with risk of a viral NADC or nonviral NADC.
Among 29,568 patients on ART, there were 410 nonviral NADCs and 213 viral NADCs. PWH with a CD4 <200 cells/µL at ART initiation had an 80% elevated risk for developing a viral NADC. Each increase of 100 cells/µL in CD4 after ART initiation decreased risk by 14%. For viral and nonviral NADCs, 10% more follow-up time spent with a CD4 >500 cells/µL was associated with decreased risk viral, adjusted hazard ratio (aHR): 0.82; 95% confidence intervals (CI): 0.78 to 0.86; nonviral, aHR: 0.88; 95% CI: 0.86 to 91, even after accounting for CD4 at ART initiation. When examining HIV control only, 10% more time with VL <50 copies/mL was significantly associated with decreased viral (aHR: 0.85; 95% CI: 0.82 to 0.89) and nonviral NADC risk (aHR: 0.88; 95% CI: 0.85 to 0.90).
This study demonstrates that even for PWH on ART therapy, maintaining HIV control is associated with lower risk of both viral and nonviral NADCs.
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