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Background. We assessed mortality attributable to smoking among patients with human immunodeficiency virus (HIV). Methods. We estimated mortality rates (MRs), mortality rate ratios (MRRs), life expectancies, life-years lost, and population-attributable risk of death associated with smoking and with HIV among current and nonsmoking individuals from a population-based, nationwide HIV cohort and a cohort of matched HIV-negative individuals. Results. A total of 2921 HIV patients and 10 642 controls were followed for 14 281 and 45 122 person-years, respectively. All-cause and non-AIDS-related mortality was substantially increased among smoking compared to nonsmoking HIV patients (MRR, 4.4 [95% confidence interval {CI}, 3.0–6.7] and 5.3 [95% CI, 3.2–8.8], respectively). Excess MR per 1000 person-years among current vs nonsmokers was 17.6 (95% CI, 13.3–21.9) for HIV patients and 4.8 (95% CI, 3.2–6.4) for controls. A 35-year-old HIV patient had a median life expectancy of 62.6 years (95% CI, 59.9–64.6) for smokers and 78.4 years (95% CI, 70.8–84.0) for nonsmokers; the numbers of life-years lost in association with smoking and HIV were 12.3 (95% CI, 8.1–16.4) and 5.1 (95% CI, 1.6–8.5). The population-attributable risk of death associated with smoking was 61.5% among HIV patients and 34.2% among controls. Conclusions. In a setting where HIV care is well organized and antiretroviral therapy is free of charge, HIV-infected smokers lose more life-years to smoking than to HIV. The excess mortality of smokers is tripled and the population-attributable risk of death associated with smoking is doubled among HIV patients compared to the background population.

Both hepatitis C virus (HCV) mono-infected and HIV/HCV co-infected patients are in need of safe, effective, all-oral HCV regimens. In a phase 2 study we aimed to assess the efficacy and safety of grazoprevir (MK-5172; HCV NS3/4A protease inhibitor) and two doses of elbasvir (MK-8742; HCV NS5A inhibitor) in patients with HCV mono-infection and HIV/HCV co-infection. The C-WORTHY study is a phase 2, multicentre, randomised controlled trial of grazoprevir plus elbasvir with or without ribavirin in patients with HCV; here, we report findings for previously untreated (genotype 1) patients without cirrhosis who were HCV mono-infected or HIV/HCV co-infected. Eligible patients were previously untreated adults aged 18 years or older with chronic HCV genoype 1 infection and HCV RNA at least 10 000 IU/mL in peripheral blood without evidence of cirrhosis, hepatocellular carcinoma, or decompensated liver disease. In part A of the study we randomly assigned HCV-mono-infected patients to receive 12 weeks of grazoprevir (100 mg) plus elbasvir (20 mg or 50 mg) with or without ribavirin (arms A1–3); in part B we assigned HCV-mono-infected patients to 8 or 12 weeks of grazoprevir (100 mg) plus elbasvir (50 mg) with or without ribavirin (arms B1–3) and HIV/HCV co-infected patients to 12 weeks of therapy with or without ribavirin. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL 12 weeks after end of treatment (SVR12). Randomisation was by presence or absence of ribavirin, 8 or 12 weeks of treatment, and dosage of elbasvir. Patients were stratified by gentoype 1a versus 1b. The patients, investigators, and study site personnel were masked to treatment group assignements but the funder was not. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01717326. 218 patients with HCV mono-infection (n=159) and HIV/HCV co-infection (n=59) were enrolled. SVR12 for patients treated for 12 weeks with or without ribavirin ranged from 93–98% in mono-infected and 87–97% in co-infected patients. SVR12 rates in mono-infected and co-infected patients treated for 12 weeks without ribavirin were 98% (95% CI 88–100; 43/44) and 87% (95% CI 69–96; 26/30), respectively, and with ribavirin were 93% (95% CI 85–97; 79/85) and 97% (95% CI 82–100; 28/29), respectively. Among mono-infected patients with genotype 1a infection treated for 8 weeks, SVR12 was 80% (95% CI 61–92; 24/30). Five of six patients who discontinued early for reasons other than virological failure had HCV RNA less than 25 IU/mL at their last study visit. Virological failure among patients treated for 12 weeks occurred in seven patients (7/188, 4%) and was associated with emergence of resistance-associated variants to one or both drugs. The safety profile of grazoprevir plus elbasvir with or without ribavirin was similar in mono-infected and co-infected patients. No patient discontinued due to an adverse event or laboratory abnormality. The most common adverse events were fatigue (51 patients, 23%), headache (44, 20%), nausea (32, 15%), and diarrhoea (21, 10%). Once-daily grazoprevir plus elbasvir with or without ribavirin for 12 weeks in previously untreated HCV-mono-infected and HIV/HCV-co-infected patients without cirrhosis achieved SVR12 rates of 87–98%. These results support the ongoing phase 3 development of grazoprevir plus elbasvir. Merck & Co, Inc.

In a nationwide, population-based cohort study we assessed the risk of diabetes mellitus (DM) in HIV-infected individuals compared with the general population, and evaluated the impact of risk factors for DM in HIV-infected individuals. We identified 4,984 Danish-born HIV-infected individuals from the Danish HIV Cohort Study and a Danish born population-based age- and gender-matched comparison cohort of 19,936 individuals (study period: 1996-2009). Data on DM was obtained from the Danish National Hospital Registry and the Danish National Prescription Registry. Incidence rate ratios (IRR) and impact of risk factors including exposure to Highly Active Antiretroviral Therapy (HAART) and antiretroviral drugs were estimated by Poisson regression analyses. In the period 1996-1999 risk of DM was higher in HIV-infected individuals compared to the comparison cohort (adjusted IRR: 2.83; 95%CI: 1.57-5.09), both before (adjusted IRR: 2.40; 95%CI: 1.03-5.62) and after HAART initiation (adjusted IRR: 3.24; 95% CI: 1.42-7.39). In the period 1999-2010 the risk of DM in HIV-infected individuals did not differ from that of the comparison cohort (adjusted IRR: 0.90; 95% CI: 0.72-1.13), although the risk was decreased before HAART-initiation (adjusted IRR: 0.45; 95%CI: 0.21-0.96). Increasing age, BMI and the presence of lipoatrophy increased the risk of DM, as did exposure to indinavir, saquinavir, stavudine and didanosine. Native HIV-infected individuals do not have an increased risk of developing DM compared to a native background population after year 1998. Some antiretroviral drugs, not used in modern antiretroviral treatment, seem to increase the risk of DM.

BACKGROUND: Osteopenia, osteoporosis, and low bone mineral density are frequent in patients with HIV. We assessed the 96 week loss of bone mineral density associated with a nucleoside or nucleotide reverse transcriptase inhibitor (NtRTI)-sparing regimen. METHODS: Antiretroviral-naive adults with HIV were enrolled in 78 clinical sites in 15 European countries into a randomised (1:1), open-label, non-inferiority trial (NEAT001/ANRS143) assessing the efficacy and safety of darunavir (800 mg once per day) and ritonavir (100 mg once per day) plus either raltegravir (400 mg twice per day; NtRTI-sparing regimen) or tenofovir (245 mg once per day) and emtricitabine (200 mg once per day; standard regimen). For this bone-health substudy, 20 of the original sites in six countries participated, and any patient enrolled at one of these sites who met the following criteria was eligible: plasma viral loads greater than 1000 HIV RNA copies per mL and CD4 cell counts of fewer than 500 cells per μL, except in those with symptomatic HIV infection. Exclusion criteria included treatment for malignant disease, testing positive for hepatitis B virus surface antigen, pregnancy, creatinine clearance less than 60 mL per min, treatment for osteoporosis, systemic steroids, or oestrogen-replacement therapy. The two primary endpoints were the mean percentage changes in lumbar spine and total hip bone mineral density at week 48, assessed by dual energy x-ray absorptiometry (DXA) scans. We did the analysis with an intention-to-treat-exposed approach with antiretroviral modifications ignored. The parent trial is registered with ClinicalTrials.gov, number NCT01066962, and is closed to new participants. FINDINGS: Between Aug 2, 2010, and April 18, 2011, we recruited 146 patients to the substudy, 70 assigned to the NtRTI-sparing regimen and 76 to the standard regimen. DXA data were available for 129, 121 and 107 patients at baseline, 48 and 96 weeks respectively. At week 48, the mean percentage loss in bone mineral density in the lumbar spine wasgreater in the standard group than in the NtRTI-sparing group (mean percentage change -2.49% vs -1.00%, mean percentage difference -1.49, 95% CI -2.94 to -0.04; p=0.046). Total hip bone mineral density loss was similarly greater at week 48 in the standard group than in the NtRTI-sparing group (mean percentage change -3.30% vs -0.73%; mean percentage difference -2.57, 95% CI -3.75 to -1.35; p<0.0001). Seven new fractures occurred during the trial (two in the NtRTI-sparing group and five in the standard group). INTERPRETATION: A raltegravir-based regimen was associated with significantly less loss of bone mineral density than a standard regimen containing tenofovir disoproxil fumarate, and might be a treatment option for patients at high risk of osteopenia or osteoporosis who are not suitable for NtRTIs such as abacavir or tenofovir alafenamide. FUNDING: The European Union Sixth Framework Programme, Inserm-ANRS, Ministerio de Sanidad y Asuntos Sociales de España, Gilead Sciences, Janssen Pharmaceuticals, andMerck Laboratories.

Worldwide, approximately 35 million individuals are infected with HIV; about 25 million of these live in sub-Saharan Africa. WHO proposes using treatment as prevention (TasP) to eliminate HIV. Treatment suppresses viral load, decreasing the probability an individual transmits HIV. The elimination threshold is one new HIV infection per 1000 individuals. Here, we test the hypothesis that TasP can substantially reduce epidemics and eliminate HIV. We estimate the impact of TasP, between 1996 and 2013, on the Danish HIV epidemic in men who have sex with men (MSM), an epidemic UNAIDS has identified as a priority for elimination. We use a CD4-staged Bayesian back-calculation approach to estimate incidence, and the hidden epidemic (the number of HIV-infected undiagnosed MSM). To develop the back-calculation model, we use data from an ongoing nationwide population-based study: the Danish HIV Cohort Study. Incidence, and the hidden epidemic, decreased substantially after treatment was introduced in 1996. By 2013, incidence was close to the elimination threshold: 1·4 (median, 95% Bayesian credible interval [BCI] 0·4–2·1) new HIV infections per 1000 MSM and there were only 617 (264–858) undiagnosed MSM. Decreasing incidence and increasing treatment coverage were highly correlated; a treatment threshold effect was apparent. Our study is the first to show that TasP can substantially reduce a country's HIV epidemic, and bring it close to elimination. However, we have shown the effectiveness of TasP under optimal conditions: very high treatment coverage, and exceptionally high (98%) viral suppression rate. Unless these extremely challenging conditions can be met in sub-Saharan Africa, the WHO's global elimination strategy is unlikely to succeed. National Institute of Allergy and Infectious Diseases.

We determined the impact of three factors on mortality in HIV-infected patients who had been on highly active antiretroviral therapy (HAART) for at least one year: (1) insufficient response to (HAART) and presence of AIDS-defining diseases, (2) comorbidity, and (3) drug and alcohol abuse and compared the mortality to that of the general population. In a Danish nationwide, population-based cohort study, we used population based registries to identify (1) all Danish HIV-infected patients who started HAART in the period 1 January 1998-1 July 2009, and (2) a comparison cohort of individuals matched on date of birth and gender (N = 2,267 and 9,068, respectively). Study inclusion began 1 year after start of HAART. Patients were categorised hierarchically in four groups according to the three risk factors, which were identified before study inclusion. The main outcome measure was probability of survival from age 25 to 65 years. The probability of survival from age 25 to age 65 was substantially lower in HIV patients [0.48 (95% confidence interval (CI) 0.42-0.55)] compared to the comparison cohort [0.88 (0.86 to 0.90)]. However, in HIV patients with no risk factors (N = 871) the probability of survival was equivalent to that of the general population [0.86 (95% CI 0.77-0.92)]. In contrast, the probability of survival was 0.58 in patients with HIV risk factors (N = 704), 0.30 in patients with comorbidities (N = 479), and 0.03 in patients with drug or alcohol abuse (N = 313). The increased risk of death in HIV-infected individuals is mainly attributable to risk factors that can be identified prior to or in the initial period of antiretroviral treatment. Mortality in patients without risk factors on a successful HAART is almost identical to that of the non-HIV-infected population.

Background Antiretroviral therapy (ART) in people with HIV (PWH) can lead to weight gain, but the effects of nucleoside reverse transcriptase inhibitors such as abacavir (ABC) are not well understood. In this study, we investigated whether discontinuing ABC would mitigate weight changes and metabolic complications in PWH. Methods In a randomized controlled trial including PWH on dolutegravir, ABC, and lamivudine (DTG/ABC/3TC), participants were randomized 2:1 to either switch to DTG/3TC or continue DTG/ABC/3TC. Data was collected at baseline, week 24, and week 48. This study was powered to detect a difference of 2 kg in weight between groups. Secondary outcomes included body composition, fat and muscle distribution, and metabolic parameters. Weight and metabolic changes were analyzed by linear mixed modeling. Results Eighty-one participants were randomized. Switching from DTG/ABC/3TC to DTG/3TC was not associated with a significant change in weight at 48 weeks in the intention to treat (ITT) analysis (mean difference − 0.5 kg, 95% confidence interval (CI): -2.5 to 1.5, p  = 0.599) or the modified ITT, (-0.1 kg, 95% CI: -1.7 to 1.5, p  = 0.914). In the ITT analysis, the DTG/3TC group gained 0.4 kg ± 5.1 SD ( p  = 0.589) compared to 0.9 kg ± 2.3 SD ( p  = 0.054) in the DTG/ABC/3TC group, while in the modified ITT, the changes were 0.9 ± 3.2 kg ( p  = 0.054) and 0.9 ± 3.6 kg ( p  = 0.071), respectively. The were no differences between groups in secondary outcomes. Conclusion Continuing or discontinuing abacavir for 48 weeks was associated with modest gains in weight that did not differ between groups. Similarly, fat distribution, or metabolic parameters were comparable between groups.

HIV-1 resistance towards integrase inhibitors is a potential threat of the success of HIV-1 combination treatment. G118R is a rare drug resistance mutation conferring pan-integrase resistance. Here, we describe the occurrence of G118R in a HIV-1 subtype-B-positive individual with major compliance problems, detected while the patient was on dolutegravir-based cART. We speculate the pre-selection of M184I/V aided the occurrence of G118R in this case, and discuss the robustness of dolutegravir-based therapies.

Background As people living with HIV (PLWH) are growing older, there is increased incidence of metabolic diseases, including type 2 diabetes mellitus, for which insulin resistance is a key determinant. In this study, we aimed to investigate risk factors associated with insulin resistance in PLWH. Methods We included well-treated PLWH without hepatitis co-infection, and with available fasting serum insulin and plasma glucose (n = 643) from the Copenhagen Comorbidity in HIV Infection Study. Insulin resistance was calculated using the homeostasis model assessment of insulin resistance (HOMA-IR). We investigated the association between risk factors and high HOMA-IR in a logistic regression model adjusted for age, sex, abdominal obesity, smoking status, and origin. When including use of thymidine analogues and/or didanosine in the model, we also adjusted for time with HIV. Results Median (IQR) age of PLWH was 52 years (46–61), and 87% (n = 557) were male. Median (IQR) HOMA-IR was 1.86 (1.23–3.14) mmol/L × mU/L. Risk factors significantly associated with high HOMA-IR included older age, BMI ≥ 25, abdominal obesity, waist circumference, use of thymidine analogues and/or didanosine, time with HIV, and CD4 + nadir < 200 cells/µL. Conclusions Insulin resistance in PLWH is associated with both use of thymidine analogues and/or didanosine and prior immunodeficiency suggesting that increased attention on blood glucose in these patients could be beneficial.

IntroductionWith longer life expectancy in people living with HIV (PLWH) on antiretroviral therapy, cardiovascular disease (CVD) has become a common cause of mortality among them. Abacavir has been associated with an increased risk of myocardial infarction, but the mechanism is unknown. Additionally, abacavir may be obesogenic which could mediate an additional risk factor of CVD. We aim to investigate if discontinuation of abacavir will have a favourable impact on body weight and cardiac parameters in PLWH.Methods and analysisRandomised, controlled, superiority trial of virologically suppressed PLWH on dolutegravir, abacavir and lamivudine (DTG/ABC/3TC) for ≥6 months. In total, 70 PLWH will be randomised 1:2 to either continue DTG/ABC/3TC or to switch to dolutegravir and lamivudine (DTG/3TC) providing the power of 80% at alpha 5% to detect a mean difference in weight change of 2 kg (Δ) given an SD of 2.7 kg. Follow-up will be 48 weeks. Data will be collected at baseline and week 48. Primary outcome will be change in mean body weight from baseline to week 24 and 48 evaluated in a linear mixed model. Secondary outcomes will be changes in cardiac, inflammatory and metabolic parameters, fat distribution, coagulation, endothelial, platelet function, quality of life and virological control from baseline to week 48. Measurements include CT of thorax and abdomen, external carotid artery ultrasound, liver elastography and dual energy X-ray absorptiometry and blood analysis. Plasma HIV RNA will be measured at baseline, week 4, 24 and 48. Forty participants (20 from each arm) will be included in a substudy involving cardiac MRI at baseline and week 48. Twenty non-HIV-infected controls will be included with a single scan to compare with baseline scan data.Ethics and disseminationResult from this study will lead to a better understanding of the association between antiretroviral therapy and the impact on weight and risk of CVD. Findings will be useful for both clinicians and PLWH in the guidance of a more individualised HIV treatment. Results from the main study and the substudies will be submitted for publication in a peer-reviewed journal(s). The AVERTAS study is approved by the Ethics Committee of the Capital Region, Denmark (H-20011433), Danish Medicines Agency (EudraCT no. 2019-004999-19) and Regional Data Protection Centre (P-2020–207).Trial registration numberPre-results registration at ClinicalTrials.gov Identifier: NCT04904406, registered 27 May 2021. Protocol version: Protocol version 9.0, 4 April 2023, approved 10-05-2023 by Ethics Committee of the Capital Region, Denmark (H-20011433). Danish Medicines Agency (EudraCT no. 2019-004999-19). Regional Data Protection Centre (P-2020–207) ClinicalTrials.gov.