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Long-Term Benefits from Early Antiretroviral Therapy Initiation in HIV Infection.
Lundgren, JD, Babiker, AG, Sharma, S, Grund, B, Phillips, AN, Matthews, G, Kan, VL, Aagaard, B, Abo, I, Alston, B, et al
NEJM evidence. 2023;(3)
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BACKGROUND For people with HIV and CD4+ counts >500 cells/mm3, early initiation of antiretroviral therapy (ART) reduces serious AIDS and serious non-AIDS (SNA) risk compared with deferral of treatment until CD4+ counts are <350 cells/mm3. Whether excess risk of AIDS and SNA persists once ART is initiated for those who defer treatment is uncertain. METHODS The Strategic Timing of AntiRetroviral Treatment (START) trial, as previously reported, randomly assigned 4684 ART-naive HIV-positive adults with CD4+ counts .500 cells/mm3 to immediate treatment initiation after random assignment (n = 2325) or deferred treatment (n= 2359). In 2015, a 57% lower risk of the primary end point (AIDS, SNA, or death) for the immediate group was reported, and the deferred group was offered ART. This article reports the follow-up that continued to December 31, 2021. Cox proportional-hazards models were used to compare hazard ratios for the primary end point from randomization through December 31, 2015, versus January 1, 2016, through December 31, 2021. RESULTS Through December 31, 2015, approximately 7 months after the cutoff date from the previous report, the median CD4+ count was 648 and 460 cells/mm3 in the immediate and deferred groups, respectively, at treatment initiation. The percentage of follow-up time spent taking ART was 95% and 36% for the immediate and deferred groups, respectively, and the time-averaged CD4+ difference was 199 cells/mm3. After January 1, 2016, the percentage of follow-up time on treatment was 97.2% and 94.1% for the immediate and deferred groups, respectively, and the CD4+ count difference was 155 cells/mm3. After January 1, 2016, a total of 89 immediate and 113 deferred group participants experienced a primary end point (hazard ratio of 0.79 [95% confidence interval, 0.60 to 1.04] versus hazard ratio of 0.47 [95% confidence interval, 0.34 to 0.65; P<0.001]) before 2016 (P=0.02 for hazard ratio difference). CONCLUSIONS Among adults with CD4+ counts >500 cells/mm3, excess risk of AIDS and SNA associated with delaying treatment initiation was diminished after ART initiation, but persistent excess risk remained. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
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Proactive Prophylaxis With Azithromycin and HydroxyChloroquine in Hospitalised Patients With COVID-19 (ProPAC-COVID): A structured summary of a study protocol for a randomised controlled trial.
Sivapalan, P, Ulrik, CS, Bojesen, RD, Lapperre, TS, Eklöf, JV, Håkansson, KEJ, Browatzki, A, Tidemansen, C, Wilcke, JT, Janner, J, et al
Trials. 2020;(1):513
Abstract
OBJECTIVES The aim of this randomised GCP-controlled trial is to clarify whether combination therapy with the antibiotic azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy and pre-emptive treatment of supra-infections can shorten hospitalisation duration for patients with COVID-19 (measured as "days alive and out of hospital" as the primary outcome), reduce the risk of non- invasive ventilation, treatment in the intensive care unit and death. TRIAL DESIGN This is a multi-centre, randomised, Placebo-controlled, 2-arm ratio 1:1, parallel group double-blind study. PARTICIPANTS 226 participants are recruited at the trial sites/hospitals, where the study will take place in Denmark: Aalborg, Bispebjerg, Gentofte, Herlev, Hillerød, Hvidovre, Odense and Slagelse hospitals. INCLUSION CRITERIA • Patient admitted to Danish emergency departments, respiratory medicine departments or internal medicine departments • Age≥ 18 years • Hospitalized ≤48 hours • Positive COVID-19 test / diagnosis during the hospitalization (confirmed). • Men or non-fertile women. Fertile women* must not be pregnant, i.e. negative pregnancy test must be available at inclusion • Informed consent signed by the patient *Defined as after menarche and until postmenopausal (no menstruation for 12 months) Exclusion criteria: • At the time of recruitment, the patient uses >5 LO2/min (equivalent to 40% FiO2 if measured) • Known intolerance/allergy to azithromycin or hydroxychloroquine or hypersensitivity to quinine or 4-aminoquinoline derivatives • Neurogenic hearing loss • Psoriasis • Retinopathy • Maculopathy • Visual field changes • Breastfeeding • Severe liver diseases other than amoebiasis (INR> 1.5 spontaneously) • Severe gastrointestinal, neurological and hematological disorders (investigator-assessed) • eGFR <45 ml/min/1.73 m2 • Clinically significant cardiac conduction disorders/arrhythmias or prolonged QTc interval (QTc (f) of> 480/470 ms). • Myasthenia gravis • Treatment with digoxin* • Glucose-6-phosphate dehydrogenase deficiency • Porphyria • Hypoglycaemia (Blood glucose at any time since hospitalization of <3.0 mmol/L) • Severe mental illness which significantly impedes cooperation • Severe linguistic problems that significantly hinder cooperation • Treatment with ergot alkaloids *The patient must not be treated with digoxin for the duration of the intervention. For atrial fibrillation/flutter, select according to the Cardiovascular National Treatment Guide (NBV): Calcium antagonist, Beta blocker, direct current (DC) conversion or amiodarone. In case of urgent need for digoxin treatment (contraindication for the aforementioned equal alternatives), the test drug should be paused, and ECG should be taken daily. INTERVENTION AND COMPARATOR Control group: The control group will receive the standard treatment + placebo for both types of intervention medication at all times. If part or all the intervention therapy being investigated becomes standard treatment during the study, this may also be offered to the control group. Intervention group: The patients in the intervention group will also receive standard care. Immediately after randomisation to the intervention group, the patient will begin treatment with: Azithromycin: Day 1-3: 500 mg x 1 Day 4-15: 250 mg x 1 If the patient is unable to take the medication orally by themselves, the medication will, if possible, be administered by either stomach-feeding tube, or alternatively, temporary be changed to clarithromycin 500 mg x 2 (this only in agreement with either study coordinator Pradeesh Sivapalan or principal investigator Jens-Ulrik Stæhr Jensen). This will also be done in the control group if necessary. The patient will switch back to azithromycin when possible. Hydroxychloroquine: Furthermore, the patient will be treated with hydroxychloroquine as follows: Day 1-15: 200 mg x 2 MAIN OUTCOMES • Number of days alive and discharged from hospital within 14 days (summarises both whether the patient is alive and discharged from hospital) ("Days alive and out of hospital") RANDOMISATION The sponsor (Chronic Obstructive Pulmonary Disease Trial Network, COP:TRIN) generates a randomisation sequence. Randomisation will be in blocks of unknown size and the final allocation will be via an encrypted website (REDCap). There will be stratification for age (>70 years vs. <=70 years), site of recruitment and whether the patient has any of the following chronic lung diseases: COPD, asthma, bronchiectasis, interstitial lung disease (Yes vs. No). BLINDING (MASKING): Participants and study personnel will both be blinded, i.e. neither will know which group the participant is allocated to. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This study requires 226 patients randomised 1:1 with 113 in each group. TRIAL STATUS Protocol version 1.8, from April 16, 2020. Recruitment is ongoing (first patient recruited April 6, 2020; final patient expected to be recruited October 31, 2020). TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04322396 (registered March 26, 2020) FULL PROTOCOL The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
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Are we successfully managing cardiovascular disease in people living with HIV?
Hatleberg, CI, Lundgren, JD, Ryom, L
Current opinion in HIV and AIDS. 2017;(6):594-603
Abstract
PURPOSE OF REVIEW The aim of this study was to discuss the most recent research in the management of cardiovascular disease (CVD) in people living with HIV (PLWHIV) with a focus on screening, primary and secondary prevention. RECENT FINDINGS The cause of CVD in PLWHIV is complex and multifactorial and creates a demand for a multifaceted approach to screening and prevention. Current screening and management of CVD risk factors in PLWHIV is suboptimal, reasons for this are not clear and the data are still scarce both in the primary and secondary preventive setting. There are no optimal routine risk screening tools available to accurately detect early and subclinical disease; PLWHIV are undertreated with preventive drugs such as statins and aspirin and antihypertensives; there are still no programmes that have been shown significantly efficient over time with regards to improved smoking cessation, increased physical activity and optimal diet, and recent reports call for intensified focus on HIV-positive women as a particularly vulnerable subgroup. SUMMARY There is a need for further studies investigating barriers to optimal CVD risk factor management in PLWHIV and an increased focus of CVD prevention in HIV-positive women.
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Longitudinal analysis of the associations between antiretroviral therapy, viraemia and immunosuppression with lipid levels: the D:A:D study.
Kamara, DA, Smith, C, Ryom, L, Reiss, P, Rickenbach, M, Phillips, A, Mocroft, A, De Wit, S, Law, M, Monforte, AD, et al
Antiviral therapy. 2016;(6):495-506
Abstract
BACKGROUND Antiretroviral (ART) drugs have been associated with higher triglycerides (TG), higher total cholesterol (TC) and lower high-density lipoprotein cholesterol (HDL-C) levels. Associations between lipid levels with HIV viraemia and immunosuppression in the presence of ART remain unclear. METHODS Participants from the D:A:D study with at least one TG/TC/HDL-C measurement were included. Linear mixed effect models were used to determine the association of ART, viral load (VL), nadir and current CD4+ T-cell count and previous AIDS diagnosis with lipids. RESULTS Of 49,717 participants, 90%, 92% and 80% contributed at least one TG/TC/HDL-C measurement (median follow-up 6.8, 6.8 and 5.0 years, respectively). Predicted mean (95% CI) baseline levels for TG, TC and HDL-C (mmol/l), were 2.10 (2.05, 2.14), 4.94 (4.91, 4.98) and 1.08 (1.07, 1.10), respectively. Lopinavir was associated with the worst TG profile, (27.2% higher levels compared to atazanavir; 95% CI 25.2%, 29.2%), and darunavir had a similar profile as atazanavir. The nucleoside pair lamivudine/tenofovir was associated with the most favourable TG profile (-2.8%; -3.5%, -2.0%) compared with emtricitabine/tenofovir, whereas lamivudine/abacavir (+10.2%; +9.3%, +11.2%) and lamivudine/stavudine (+8.0%; +6.9%, +9.0%), were associated with the worst. Raltegravir was associated with lower TG (-5.2%; -6.4%, -3.9%), and nevirapine had a more favourable HDL-C profile (+11.3%; +10.8%, +11.7%) than efavirenz (+5.3%; 5.0%, 5.7%), compared to atazanavir. Higher VLs were associated with lower TG/TC/HDL-C, whereas higher CD4+ T-cell counts were associated with higher TG/TC/HDL-C. CONCLUSIONS TG, TC and HDL-C levels, which generally improved over time, are dependent on ART, viraemia and, to a lesser extent, immunosuppression.
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Nonnucleoside Reverse-transcriptase Inhibitor- vs Ritonavir-boosted Protease Inhibitor-based Regimens for Initial Treatment of HIV Infection: A Systematic Review and Metaanalysis of Randomized Trials.
Borges, ÁH, Lundh, A, Tendal, B, Bartlett, JA, Clumeck, N, Costagliola, D, Daar, ES, Echeverría, P, Gisslén, M, Huedo-Medina, TB, et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2016;(2):268-80
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BACKGROUND Previous studies suggest that nonnucleoside reverse-transcriptase inhibitors (NNRTIs) cause faster virologic suppression, while ritonavir-boosted protease inhibitors (PI/r) recover more CD4 cells. However, individual trials have not been powered to compare clinical outcomes. METHODS We searched databases to identify randomized trials that compared NNRTI- vs PI/r-based initial therapy. A metaanalysis calculated risk ratios (RRs) or mean differences (MDs), as appropriate. Primary outcome was death or progression to AIDS. Secondary outcomes were death, progression to AIDS, and treatment discontinuation. We calculated RR of virologic suppression and MD for an increase in CD4 cells at week 48. RESULTS We included 29 trials with 9047 participants. Death or progression to AIDS occurred in 226 participants in the NNRTI arm and in 221 in the PI/r arm (RR, 1.03; 95% confidence interval, .87-1.22; 12 trials; n = 3825), death in 205 participants in the NNRTI arm vs 198 in the PI/r arm (1.04; 0.86-1.25; 22 trials; n = 8311), and progression to AIDS in 140 participants in the NNRTI arm vs 144 in the PI/r arm (1.00; 0.80-1.25; 13 trials; n = 4740). Overall treatment discontinuation (1.12; 0.93-1.35; 24 trials; n = 8249) and from toxicity (1.21; 0.87-1.68; 21 trials; n = 6195) were comparable, but discontinuation due to virologic failure was more common with NNRTI (1.58; 0.91-2.74; 17 trials; n = 5371). At week 48, there was no difference between NNRTI and PI/r in virologic suppression (RR, 1.03; 0.98-1.09) or CD4(+) recovery (MD, -4.7 cells; -14.2 to 4.8). CONCLUSIONS We found no difference in clinical and viro-immunologic outcomes between NNRTI- and PI/r-based therapy.
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Albert J. Stunkard: His Research on Obesity and Its Psychological Impact.
Allison, KC, Lundgren, JD, Wadden, TA
Current obesity reports. 2016;(1):140-4
Abstract
Albert J. ("Mickey") Stunkard, MD, was a leader in the field of obesity research, with his work spanning more than five decades. He published several groundbreaking findings on the psychosocial influences of obesity, the genetics of obesity, and the relationship between obesity and factors such as socioeconomic status, stigma, and mood. He also helped establish two eating disorders associated with obesity-binge eating disorder and night eating syndrome. This paper highlights his work and its implications for the field.
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Platelet count kinetics following interruption of antiretroviral treatment.
Zetterberg, E, Neuhaus, J, Baker, JV, Somboonwit, C, Llibre, JM, Palfreeman, A, Chini, M, Lundgren, JD, ,
AIDS (London, England). 2013;(1):59-68
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OBJECTIVES To investigate the mechanisms of platelet kinetics in the Strategies for Management of Antiretroviral Therapy (SMART) study that demonstrated excess mortality with CD4 guided episodic antiretroviral therapy (ART) drug conservation compared with continuous treatment viral suppression. Follow-up analyses of stored plasma samples demonstrated increased activation of both inflammatory and coagulation pathways after stopping ART. DESIGN SMART patients from sites that determined platelets routinely. METHODS Platelet counts were retrospectively collected from 2206 patients from visits at study entry, and during follow-up. D-dimer levels were measured at study entry, month 1, and 2. RESULTS Platelet levels decreased in the drug conservation group following randomization, but remained stable in the viral suppression group [median (IQR) decline from study entry to month 4: -24 000/μl (-54 000 to 4000) vs. 3000 (-22 000 to 24 000), respectively, P < 0.0001)] and the rate of developing thrombocytopenia (<100 000/μl) was significantly higher in the drug conservation vs. the viral suppression arm (unadjusted drug conservation/viral suppression [HR (95%CI) = 1.8 (1.2-2.7)]. The decline in platelet count among drug conservation participants on fully suppressive ART correlated with the rise in D-dimer from study entry to either month 1 or 2 (r = -0.41; P = 0.02). Among drug conservation participants who resumed ART 74% recovered to their study entry platelet levels. CONCLUSION Interrupting ART increases the risk of thrombocytopenia, but reinitiation of ART typically reverses it. Factors contributing to declines in platelets after interrupting ART may include activation of coagulation pathways or HIV-1 replication itself. The contribution of platelets in HIV-related procoagulant activity requires further study.
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Implementing the number needed to harm in clinical practice: risk of myocardial infarction in HIV-1-infected patients treated with abacavir.
Kowalska, JD, Kirk, O, Mocroft, A, Høj, L, Friis-Møller, N, Reiss, P, Weller, I, Lundgren, JD
HIV medicine. 2010;(3):200-8
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OBJECTIVES The D:A:D study group reported a 1.9-fold increased relative risk (RR) of myocardial infarction (MI) associated with current or recent use of abacavir. The number needed to harm (NNH) incorporates information about the underlying risk of MI and the increased RR of MI in patients taking abacavir. METHODS NNH was calculated as the reciprocal of the difference between the underlying risks of MI with and without abacavir use. A parametric statistical model was used to calculate the underlying risk of MI over 5 years. RESULTS The relationship between NNH and underlying risk of MI is reciprocal, resulting in wide variation in the NNH with small changes in underlying risk of MI. The smallest changes in NNH are in the medium- and high-risk groups of MI. The NNH changes as risk components are modified; for example, for a patient who smokes and has a systolic blood pressure (sBP) of 160 mmHg and a 5-year risk of MI of 1.3% the NNH is 85, but the NNH increases to 277 if the patient is a nonsmoker and to 370 if sBP is within the normal range (120 mmHg). CONCLUSIONS We have illustrated that the impact of abacavir use on risk of MI varies according to the underlying risk and it may be possible to increase considerably the NNH by decreasing the underlying risk of MI using standard of care interventions, such as smoking cessation or control of hypertension.
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Cognitive behavior therapy for night eating syndrome: a pilot study.
Allison, KC, Lundgren, JD, Moore, RH, O'Reardon, JP, Stunkard, AJ
American journal of psychotherapy. 2010;(1):91-106
Abstract
Because no studies of psychotherapy treatments for night eating syndrome (NES) have been published, we conducted a pilot study of a 10-session cognitive behavior therapy (CBT) for NES. Twenty-five patients (19 female, 6 male) were screened and comprehensively assessed before being enrolled. At each visit, patients completed the Night Eating Symptom Scale (NESS), were weighed, and number of awakenings and the number of nocturnal ingestions and daily caloric intake were calculated from weekly food and sleep records. Mixed model regression analyses [of the data] showed significant decreases in caloric intake after dinner (35.0% to 24.9%); number of nocturnal ingestions (8.7 to 2.6 per week); weight (82.5 to 79.4 kg); and NESS score (28.7 to 16.3; all p values <0.0001). Number of awakenings per week, depressed mood, and quality of life also improved significantly (p values <.02). This first clinical trial of CBT for NES shows significant improvements in the core aspects of NES and weight reduction, suggesting the need for a controlled treatment trial.
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Remission of metabolic syndrome following a 15-week low-calorie lifestyle change program for weight loss.
Lundgren, JD, Malcolm, R, Binks, M, O'Neil, PM
International journal of obesity (2005). 2009;(1):144-50
Abstract
OBJECTIVE To evaluate the rate of remission of metabolic syndrome (Met Syn) among patients undergoing a brief, low-calorie lifestyle change weight loss intervention and to compare the baseline characteristics of patients who were remitted and not remitted from Met Syn at post-treatment. RESEARCH METHODS AND PROCEDURES Obese adults (N=36) meeting criteria for Met Syn enrolled in an outpatient fee-for-service behavioral weight loss intervention. Participants were assessed on key Met Syn variables (waist circumference, blood pressure, triglycerides, high-density lipoprotein (HDL) cholesterol and fasting blood glucose) at pre- and post-treatment. RESULTS The majority of patients (61%) responded to treatment after a 9.9% mean weight loss. Although Met Syn responders did not differ significantly from Met Syn non-responders on any baseline Met Syn criterion variable, responders had significantly lower baseline body mass indices (BMI; kg/m(2)) and met criteria for fewer baseline Met Syn variables. As expected, Met Syn responders, compared with Met Syn non-responders, had significantly lower post-treatment waist circumference, systolic and diastolic blood pressures, triglycerides and fasting blood glucose. Patient groups did not differ significantly on weight lost (kg or %), or on the proportion of patients losing > or =10% of initial body weight. DISCUSSION In a community population, Met Syn responds to weight loss through a low-calorie lifestyle intervention; for some patients, however, the recommended 10% weight loss may not be enough for Met Syn remission.