The Canadian Rheumatology Association (CRA) has developed recommendations for the pharmacological management of rheumatoid arthritis (RA) with traditional and biologic disease-modifying antirheumatic ...drugs (DMARD) in 2 parts. Part 1 is reported here.
The CRA Therapeutics Committee assembled a national working group of RA clinical experts, researchers, patient consumers, and a general practitioner. Treatment questions were developed a priori based on results of a national needs assessment survey. A systematic review of all clinical practice guidelines and consensus statements regarding treatment with traditional and biologic DMARD in patients with RA published between January 2000 and June 2010 was performed in Medline, Embase, and CINAHL databases, and the grey literature. Guideline quality was assessed by 2 independent reviewers, and guideline characteristics, recommendations, and supporting evidence from observational studies and randomized controlled trials were synthesized into evidence tables. The full working group reviewed the evidence tables and developed recommendations using a modified Delphi technique.
Five overarching principles and 26 recommendations addressing general RA management strategies and treatment with glucocorticoids and traditional and biologic DMARD were developed for rheumatologists, other primary prescribers of RA drug therapies, and patients with RA.
These recommendations were developed based on a synthesis of international guidelines, supporting evidence, and expert consensus considering the Canadian healthcare context with the intention of promoting best practices and improving healthcare delivery for persons with RA.
To describe pubertal growth spurts among adolescents living with perinatally acquired HIV (ALWPHIV) on antiretroviral therapy (ART).
Observational data collected from 1994 to 2015 in the CIPHER ...global cohort collaboration.
ALWPHIV who initiated ART age less than 10 years with at least four height measurements age at least 8 years were included. Super Imposition by Translation And Rotation (SITAR) models, with parameters representing timing and intensity of the growth spurt, were used to describe growth, separately by sex. Associations between region, ART regimen, age, height-for-age (HAZ), and BMI-for-age z -scores (BMIz) at ART initiation (baseline) and age 10 years, and SITAR parameters were explored.
Four thousand seven hundred and twenty-three ALWPHIV were included: 51% from East and Southern Africa (excluding Botswana and South Africa), 17% Botswana and South Africa, 6% West and Central Africa, 11% Europe and North America, 11% Asia-Pacific, and 4% Central, South America, and Caribbean. Growth spurts were later and least intense in sub-Saharan regions. In females, older baseline age and lower BMIz at baseline were associated with later and more intense growth spurts; lower HAZ was associated with later growth spurts. In males, older baseline age and lower HAZ were associated with later and less intense growth spurts; however, associations between baseline HAZ and timing varied by age. Lower HAZ and BMIz at 10 years were associated with later and less intense growth spurts in both sexes.
ALWPHIV who started ART at older ages or already stunted were more likely to have delayed pubertal growth spurts. Longer-term follow-up is important to understand the impact of delayed growth.
Objective Characteristics of Canadian RA patients started on anti-tumor necrosis factor (TNF) treatment were compared with 12 other countries. Methods Data from the Optimization of HUMIRA trial (OH) ...were compared with Canadian real world studies Ontario Biologics Research Initiative (OBRI) and the Real-Life Evaluation of Rheumatoid Arthritis in Canadians Receiving HUMIRA (REACH), and to data from American, Australian, British, Czech, Danish, Dutch, Finnish, German, Italian, Norwegian, Spanish, and Swedish RA databases. Patient characteristics and temporal trends at initiation of anti-TNF therapy were compared between countries. Results Baseline Disease Activity Scores (DAS28) varied from 5.3 to 6.6. Lower disease severity was noted in databases from countries with less restrictive anti-TNF coverage: Dutch based on previous disease-modifying antirheumatic drugs (DMARD) use, DAS28, swollen joint count (SJC), tender joint count (TJC), Health Assessment Questionnaire Disability Index (HAQ-DI), Danish (previous DMARD use, DAS28), Norwegian (DAS28, SJC, TJC, visual analog scale (VAS) of global health), and Swedish (DAS28, SJC, TJC, HAQ-DI). RA databases showed lower disease scores than did OH ( P < 0.05). The US databases also showed lower disease severity (CORRONA: previous DMARD use, SJC, TJC; National Data Bank for Rheumatic Diseases: HAQ, P < 0.001). The UK and Czech Republic had restrictive coverage and higher mean baseline DAS28 than OH ( P < 0.001). Baseline DAS28 in the registries with published data lowered over time (British, Norwegian, Danish, and Swedish) but less for the British ( P < 0.001). Conclusions These results confirm that regional variation exists between the 13 countries analyzed in the initiation of treatment with anti-TNF agents among RA patients and suggest that in some cases this variation may be increasing. In some countries the mean baseline disease severity declined over time and regional reimbursement policies and differences in physician preferences may be influencing initiation of anti-TNF therapy in RA.
Published estimates of mortality and progression to AIDS as children with HIV approach adulthood are limited. We describe rates and risk factors for death and AIDS-defining events in children and ...adolescents after initiation of combination antiretroviral therapy (cART) in 17 middle- and high-income countries, including some in Western and Central Europe (W&CE), Eastern Europe (Russia and Ukraine), and Thailand.
Children with perinatal HIV aged <18 years initiating cART were followed until their 21st birthday, transfer to adult care, death, loss to follow-up, or last visit up until 31 December 2013. Rates of death and first AIDS-defining events were calculated. Baseline and time-updated risk factors for early/late (≤/>6 months of cART) death and progression to AIDS were assessed. Of 3,526 children included, 32% were from the United Kingdom or Ireland, 30% from elsewhere in W&CE, 18% from Russia or Ukraine, and 20% from Thailand. At cART initiation, median age was 5.2 (IQR 1.4-9.3) years; 35% of children aged <5 years had a CD4 lymphocyte percentage <15% in 1997-2003, which fell to 15% of children in 2011 onwards (p < 0.001). Similarly, 53% and 18% of children ≥5 years had a CD4 count <200 cells/mm3 in 1997-2003 and in 2011 onwards, respectively (p < 0.001). Median follow-up was 5.6 (2.9-8.7) years. Of 94 deaths and 237 first AIDS-defining events, 43 (46%) and 100 (42%) were within 6 months of initiating cART, respectively. Multivariable predictors of early death were: being in the first year of life; residence in Russia, Ukraine, or Thailand; AIDS at cART start; initiating cART on a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen; severe immune suppression; and low BMI-for-age z-score. Current severe immune suppression, low current BMI-for-age z-score, and current viral load >400 c/mL predicted late death. Predictors of early and late progression to AIDS were similar. Study limitations include incomplete recording of US Centers for Disease Control (CDC) disease stage B events and serious adverse events in some countries; events that were distributed over a long time period, and that we lacked power to analyse trends in patterns and causes of death over time.
In our study, 3,526 children and adolescents with perinatal HIV infection initiated antiretroviral therapy (ART) in countries in Europe and Thailand. We observed that over 40% of deaths occurred ≤6 months after cART initiation. Greater early mortality risk in infants, as compared to older children, and in Russia, Ukraine, or Thailand as compared to W&CE, raises concern. Current severe immune suppression, being underweight, and unsuppressed viral load were associated with a higher risk of death at >6 months after initiation of cART.
Background. We compared Kaposi sarcoma (KS) risk in adults who started antiretroviral therapy (ART) across the Asia-Pacific, South Africa, Europe, Latin, and North America. Methods. We included ...cohort data of human immunodeficiency virus (HIV)–positive adults who started ART after 1995 within the framework of 2 large collaborations of observational HIV cohorts. We present incidence rates and adjusted hazard ratios (aHRs). Results. We included 208 140 patients from 57 countries. Over a period of 1 066 572 person-years, 2046 KS cases were diagnosed. KS incidence rates per 100 000 person-years were 52 in the Asia-Pacific and ranged between 180 and 280 in the other regions. KS risk was 5 times higher in South African women (aHR, 4.56; 95% confidence intervals CI, 2.73–7.62) than in their European counterparts, and 2 times higher in South African men (2.21; 1.34–3.63). In Europe, Latin, and North America KS risk was 6 times higher in men who have sex with men (aHR, 5.95; 95% CI, 5.09–6.96) than in women. Comparing patients with current CD4 cell counts ≥700 cells/μL with those whose counts were <50 cells/μL, the KS risk was halved in South Africa (aHR, 0.53; 95% CI, .17–1.63) but reduced by ≥95% in other regions. Conclusions. Despite important ART-related declines in KS incidence, men and women in South Africa and men who have sex with men remain at increased KS risk, likely due to high human herpesvirus 8 coinfection rates. Early ART initiation and maintenance of high CD4 cell counts are essential to further reducing KS incidence worldwide, but additional measures might be needed, especially in Southern Africa.
Abstract
In countries with high human immunodeficiency virus (HIV) prevalence, up to 30% of pregnant women are living with HIV, with fetal exposure to both HIV and antiretroviral therapy during ...pregnancy. In addition, pregnant women without HIV but at high risk of HIV acquisition are increasingly receiving HIV preexposure antiretroviral prophylaxis (PrEP). Investments are being made to establish and follow cohorts of children to evaluate the long-term effects of in utero HIV and antiretroviral exposure. Agreement on a key set of definitions for relevant exposures and outcomes is important both for interpreting individual study results and for comparisons across cohorts. Harmonized definitions of in utero HIV and antiretroviral drug (maternal treatment or PrEP) exposure will also facilitate improved classification of these exposures in future observational studies and clinical trials. The proposed definitions offer a uniform approach to facilitate the consistent description and estimation of effects of HIV and antiretroviral exposures on key child health outcomes.
In countries with high human immunodeficiency virus (HIV) prevalence, 20%–30% of pregnant women have HIV and receive antiretrovirals. Proposed definitions offer a uniform approach to describing/estimating the effects of in utero HIV and antiretroviral exposure on child health outcomes.
The intermediate filament (IF)-binding protein desmoplakin (DP) is essential for desmosome function and tissue integrity, but its role in junction assembly is poorly understood. Using time-lapse ...imaging, we show that cell-cell contact triggers three temporally overlapping phases of DP-GFP dynamics: (1) the de novo appearance of punctate fluorescence at new contact zones after as little as 3 min; (2) the coalescence of DP and the armadillo protein plakophilin 2 into discrete cytoplasmic particles after as little as 15 min; and (3) the cytochalasin-sensitive translocation of cytoplasmic particles to maturing borders, with kinetics ranging from 0.002 to 0.04 microm/s. DP mutants that abrogate or enhance association with IFs exhibit delayed incorporation into junctions, altering particle trajectory or increasing particle pause times, respectively. Our data are consistent with the idea that DP assembles into nascent junctions from both diffusible and particulate pools in a temporally overlapping series of events triggered by cell-cell contact and regulated by actin and DP-IF interactions.
Abstract
Background
Recent studies have shown a decrease in CD4 count during adolescence in young people with perinatally acquired human immunodeficiency virus (HIV, PHIV).
Methods
Young people with ...PHIV in the United Kingdom, followed in the Collaborative HIV Paediatric Study who started antiretroviral therapy (ART) from 2000 onward were included. Changes in CD4 count over time from age 10 to 20 years were analyzed using mixed-effects models, and were compared to published CD4 data for the gerneral population. Potential predictors were examined and included demographics, age at ART start, nadir CD4 z score (age-adjusted) in childhood, and time-updated viral load.
Results
Of 1258 young people with PHIV included, 669 (53%) were female, median age at ART initiation was 8.3 years, and the median nadir CD4 z score was −4.0. Mean CD4 count was higher in young people with PHIV who started ART before age 10 years and had a nadir CD4 z score ≥−4; these young people with PHIV had a decline in CD4 count after age 10 that was comparable to that of the general population. Mean CD4 count was lower in young people with PHIV who had started ART before age 10 and had a nadir CD4 z score <−4; for this group, the decline in CD4 count after age 10 was steeper over time.
Conclusions
In children, in addition to starting ART at an early age, optimizing ART to maintain a higher CD4 z score during childhood may be important to maximizing immune reconstitution later in life.
Young people with human immunodeficiency virus who started antiretroviral therapy before age 10 years and had a nadir CD4 z score <-4 in childhood, had a decline in CD4 count after age 10 steeper than that of the general population.
Graphical Abstract
Graphical Abstract
This graphical abstract is also available at Tidbit: https://tidbitapp.io/tidbits/evolution-of-cd4-t-cell-count-with-age-in-a-cohort-of-young-people-growing-up-with-perinatally-acquired-hiv-e628fcfc-4e7a-4d1f-b878-ebf12b31f134
A persistently low CD4/CD8 ratio has been reported to inversely correlate with the risk of non-AIDS defining cancer in people living with human immunodeficiency virus (HIV; PLWH) efficiently treated ...by combination antiretroviral therapy (cART). We evaluated the impact of the CD4/CD8 ratio on the risk of Kaposi sarcoma (KS) or non-Hodgkin lymphoma (NHL), still among the most frequent cancers in treated PLWH.
PLWH from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) were included if they achieved virological control (viral load ≤ 500 copies/mL) within 9 months following cART and without previous KS/LNH diagnosis. Cox models were used to identify factors associated with KS or NHL risk, in all participants and those with CD4 ≥ 500/mm3 at virological control. We analyzed the CD4/CD8 ratio, CD4 count and CD8 count as time-dependent variables, using spline transformations.
We included 56 708 PLWH, enrolled between 2000 and 2014. At virological control, the median (interquartile range IQR) CD4 count, CD8 count, and CD4/CD8 ratio were 414 (296-552)/mm3, 936 (670-1304)/mm3, and 0.43 (0.28-0.65), respectively. Overall, 221 KS and 187 NHL were diagnosed 9 (2-37) and 18 (7-42) months after virological control. Low CD4/CD8 ratios were associated with KS risk (hazard ratio HR = 2.02 95% confidence interval {CI } = 1.23-3.31) when comparing CD4/CD8 = 0.3 to CD4/CD8 = 1) but not with NHL risk. High CD8 counts were associated with higher NHL risk (HR = 3.14 95% CI = 1.58-6.22) when comparing CD8 = 3000/mm3 to CD8 = 1000/mm3). Similar results with increased associations were found in PLWH with CD4 ≥ 500/mm3 at virological control (HR = 3.27 95% CI = 1.60-6.56 for KS; HR = 5.28 95% CI = 2.17-12.83 for NHL).
Low CD4/CD8 ratios and high CD8 counts despite effective cART were associated with increased KS/NHL risks respectively, especially when CD4 ≥ 500/mm3.
Background
Etravirine (ETR) is approved as a component of second or third-line antiretroviral treatment (ART) for children living with HIV. We assessed the outcomes of ETR-based ART in children in ...routine care in Europe and Thailand.
Methods
Data on children aged <18 years at ETR start were pooled from 17 observational cohorts. Characteristics at ETR start, immunological and virological outcomes at 12 months, discontinuations, adverse events (AEs) and serious adverse events (SAEs) were described. Follow-up was censored at ETR discontinuation, death or last visit.
Results
177 children ever received ETR. At ETR start, median IQR age was 15 12,16 years, CD4 count 480 287, 713 cells/mm3, 70% had exposure to ≥3 ART classes and 20% had viral load (VL) <50 copies/mL. 95% received ETR in combination with ≥1 potent drug class, mostly protease inhibitor-based regimens. Median time on ETR was 24 7, 48 months. Amongst those on ETR at 12 months (n=141), 69% had VL<50 copies/mL. Median CD4 increase since ETR start (n=83) was 147 16, 267 cells/mm3. Overall, 81 (46%) discontinued ETR by last follow-up. Median time to discontinuation was 23 8, 47 months. Common reasons for discontinuation were treatment simplification (19%), treatment failure (16%) and toxicity (12%). Eight children (5%) had AEs causally associated with ETR, all dermatological/hypersensitivity reactions. Two were SAEs, both Stevens–Johnson Syndrome in children on regimens containing ETR and darunavir and were causally related to either drugs; both resolved following ART discontinuation.
Conclusion
Children receiving ETR were predominantly highly treatment-experienced, over two-thirds were virally suppressed at 12 months.
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