Hypothetical questionnaires may overestimate willingness to participate in HIV cure research: Comparison of a cross-sectional survey to actual willingness to participate in an HIV cure study in the Netherlands

Objective: Little is known about willingness among people living with HIV (PLHIV) to participate in HIV cure research in the Netherlands. We compared results of a cross-sectional questionnaire assessing hypothetical willingness to actual willingness among PLHIV to take part in a clinical HIV cure trial. Methods: Between March and June 2018, PLHIV visiting the outpatient clinic of a university hospital in the Netherlands were asked to complete a questionnaire about HIV cure research. Results were compared to the number of PLHIV willing to take part in an actual HIV cure study at the same center during an overlapping time period. Results: In total, 165 participants, predominantly male (80%) from Western European countries (61%) completed the questionnaire. The majority would participate in cure research (n ¼ 111, 67%). Separately, actual willingness among PLHIV to participate in an HIV cure study was addressed in 312 cases. Apart from gender (96% male), baseline characteristics were comparable. Less than half expressed actual willingness to participate in the study (n ¼ 135, 43%). Conclusions: Hypothetical willingness to participate in cure-related research was high among PLHIV who completed the questionnaire. Actual willingness among eligible PLHIV to take part in an HIV cure study was much lower. Our findings show that questionnaires may overestimate willingness to part

Partner notification for reduction of HIV-1 transmission and related costs among men who have sex with men: A mathematical modeling study

Background Earlier antiretroviral treatment initiation prevents new HIV infections. A key problem in HIV prevention and care is the high number of patients diagnosed late, as these undiagnosed patients can continue forward HIV transmission. We modeled the impact on the Dutch menwho-have-sex-with-men (MSM) HIV epidemic and cost-effectiveness of an existing partner notification process for earlier identification of HIV-infected individuals to reduce HIV transmission. Methods Reduction in new infections and cost-effectiveness ratios were obtained for the use of partner notification to identify 5% of all new diagnoses (Scenario 1) and 20% of all new diagnoses (Scenario 2), versus no partner notification. Costs and quality adjusted life years (QALYs) were assigned to each disease state and calculated over 5 year increments for a20 year period. Results Partner notification is predicted to avert 18-69 infections (interquartile range [IQR] 13-24; 51-93) over the course of 5 years countrywide to 221-830 (IQR 140-299; 530-1,127) over 20 years for Scenario 1 and 2 respectively. Partner notification was considered cost-effective in the short term, with increasing cost-effectiveness over time: from €41,476 -€41, 736 (IQR €40,529-€42,147; €40,791-€42,397) to €5,773 -€5,887 (€5,134-€7,196; €5,411-€6,552) per QAL

Risk of recurrent venous thromboembolism in patients with HIV infection:A nationwide cohort study

Background Multiple studies have described a higher incidence of venous thromboembolism (VTE) in people living with an HIV infection (PWH). However, data on the risk of recurrent VTE in this population are lacking, although this question is more important for clinical practice. This study aims to estimate the risk of recurrent VTE in PWH compared to controls and to identify risk factors for recurrence within this population. Methods and findings PWH with a first VTE were derived from the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort (2003-2015), a nationwide ongoing cohort following up PWH in care in the Netherlands. Uninfected controls were derived from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) follow-up study (19992003), a cohort of patients with a first VTE who initially participated in a case-control study in the Netherlands who were followed up for recurrent VTE. Selection was limited to persons with an index VTE suffering from deep vein thrombosis in the lower limbs and/or pulmonary embolism (PE). Participants were followed from withdrawal of anticoagulation to VTE recurrence, loss to follow-up, death, or end of study. We estimated incidence rates, cumulative incidence (accounting for competing risk of death) and hazard ratios (HRs) using Cox proportional hazards regression, adjusting for age, sex, and whether the index event was provoked or unprovoked. When analyzing risk factors among PWH, the main focus of analysis was the role of immune markers (cluster of differentiation 4 [CD4]+ T-cell count). There were 153 PWH (82% men, median 48 years) and 4,005 uninfected controls (45% men, median 49 years) with a first VTE (71% unprovoked in PWH, 34% unprovoked in controls) available for analysis. With 40 VTE recurrences during 774 person-years of follow-up (PYFU) in PWH and 635 VTE recurrences during 20,215 PYFU in controls, the incidence rates were 5.2 and 3.1 per 100 PYFU (HR: 1.70, 95% CI 1.23-2.36, p = 0.003). VTE consistently recurred more frequently per 100 PYFU in PWH in all predefined subgroups of men (5.6 versus 4.8), women (3.6 versus 1.9), and unprovoked (6.0 versus 5.2) or provoked (3.1 versus 2.1) first VTE. After adjustment, the VTE recurrence risk was higher in PWH compared to controls in the first year after anticoagulant discontinuation (HR: 1.67, 95% CI 1.04-2.70, p = 0.03) with higher cumulative incidences in PWH at 1 year (12.5% versus 5.6%) and 5 years (23.4% versus 15.3%) of follow-up. VTE recurred less frequently in PWH who were more immunodeficient at the first VTE, marked by a better CD4+ T-cell recovery on antiretroviral therapy and during anticoagulant therapy for the first VTE (adjusted HR: 0.81 per 100 cells/mm3 increase, 95% CI 0.67-0.97, p = 0.02). Sensitivity analyses addressing potential sources of bias confirmed our principal analyses. The main study limitations are that VTEs were adjudicated differently in the cohorts and that diagnostic practices changed during the 20-year study period. Conclusions Overall, the risk of recurrent VTE was elevated in PWH compared to controls. Among PWH, recurrence risk appeared to decrease with greater CD4+ T-cell recovery after a first VTE. This is relevant when deciding to (dis)continue anticoagulant therapy in PWH with otherwise unprovoked first VTE. Author summary Why was this study done? The HIV pandemic affects approximately 40 million people and causes significant morbidity, including a markedly increased risk of a venous thromboembolism (VTE). The recurrence risk of VTE in people living with HIV (PWH) is unknown, although this risk drives the anticoagulant therapy duration after a first VTE. Our study determined the recurrent VTE risk in PWH compared to uninfected controls. What did the researchers do and find? We performed an observational cohort study using data from the national ATHENA PWH cohort (2003-2015) in the Netherlands and the Dutch Multiple Environmenta

The risk of non-AIDS defining events is lower in ART-naive HIV controllers than in normal progressors on suppressive ART

Background. We aimed to compare the non-AIDS event (nADE) risk between normal progressors using antiretroviral therapy (NP-ART) and people with human immunodeficiency virus (HIV, PWH) who naturally control HIV infection (HIV controllers), as well as the risk of nADE following ART in HIV controllers. Methods. The primary end point was the composite of cardiovascular disease, non-AIDS malignancy, or all-cause mortality, whichever came first. The role of ART in HIV controllers was assessed as a time-varying covariate. Results. We included 1007 ART-naive HIV controllers (60 of them were elite controllers), 1510 early-ART (<6 months after negative HIV test), and 15437 NP-ART (reference group), contributing 3813, 11 060, and 160 050 years of follow-up, respectively. HIV controllers had lower risk of the primary end point (hazard ratio [HR], 0.55; 95% confidence interval [CI]: .38-.81; P = .0023), all-cause mortality (adjusted HR [aHR], 0.45; 95% CI: .25-.79; P = .0054), and cardiovascular disease (aHR, 0.47; 95% CI: .22-.99; P = .046), but not non-AIDS malignancy (aHR, 0.74; 95% CI: .41-1.35; P = .33), compared with NP-ART. Among HIV controllers, each log(10 )lower baseline viral load further decreased the risk of a nADE (aHR, 0.54; 95% CI: .29-.99; P = .045). ART in HIV controllers did not reduce the risk of any nADE (aHR, 1.22; 95% CI: .66-2.29; P = .53). Conclusions. HIV controllers had a lower n ADE risk than NP-ART, especially in those with low plasma viral loads. ART did not alter the nADE risk in HIV controllers. Our findings help clinicians to decide on prescribing ART in HIV controllers

Levels of Fibrinogen Variants Are Altered in Severe COVID-19

Background  Fibrinogen variants as a result of alternative messenger RNA splicing or protein degradation can affect fibrin(ogen) functions. The levels of these variants might be altered during coronavirus disease 2019 (COVID-19), potentially affecting disease severity or the thrombosis risk. Aim  To investigate the levels of fibrinogen variants in plasma of patients with COVID-19. Methods  In this case-control study, we measured levels of functional fibrinogen using the Clauss assay. Enzyme-linked immunosorbent assays were used to measure antigen levels of total, intact (nondegraded Aα chain), extended Aα chain (α E ), and γ' fibrinogen in healthy controls, patients with pneumococcal infection in the intensive care unit (ICU), ward patients with COVID-19, and ICU patients with COVID-19 (with and without thrombosis, two time points). Results  Healthy controls and ward patients with COVID-19 ( n  = 10) showed similar fibrinogen (variant) levels. ICU patients with COVID-19 who later did ( n  = 19) or did not develop thrombosis ( n  = 18) and ICU patients with pneumococcal infection ( n  = 6) had higher absolute levels of functional, total, intact, and α E fibrinogen than healthy controls ( n  = 7). The relative α E fibrinogen levels were higher in ICU patients with COVID-19 than in healthy controls, while relative γ' fibrinogen levels were lower. After diagnosis of thrombosis, only the functional fibrinogen levels were higher in ICU patients with COVID-19 and thrombosis than in those without, while no differences were observed in the other fibrinogen variants. Conclusion  Our results show that severe COVID-19 is associated with increased levels of α E fibrinogen and decreased relative levels of γ' fibrinogen, which may be a cause or consequence of severe disease, but this is not associated with the development of thrombosis.</p

Levels of Fibrinogen Variants Are Altered in Severe COVID-19

Background  Fibrinogen variants as a result of alternative messenger RNA splicing or protein degradation can affect fibrin(ogen) functions. The levels of these variants might be altered during coronavirus disease 2019 (COVID-19), potentially affecting disease severity or the thrombosis risk. Aim  To investigate the levels of fibrinogen variants in plasma of patients with COVID-19. Methods  In this case-control study, we measured levels of functional fibrinogen using the Clauss assay. Enzyme-linked immunosorbent assays were used to measure antigen levels of total, intact (nondegraded Aα chain), extended Aα chain (α E ), and γ' fibrinogen in healthy controls, patients with pneumococcal infection in the intensive care unit (ICU), ward patients with COVID-19, and ICU patients with COVID-19 (with and without thrombosis, two time points). Results  Healthy controls and ward patients with COVID-19 ( n  = 10) showed similar fibrinogen (variant) levels. ICU patients with COVID-19 who later did ( n  = 19) or did not develop thrombosis ( n  = 18) and ICU patients with pneumococcal infection ( n  = 6) had higher absolute levels of functional, total, intact, and α E fibrinogen than healthy controls ( n  = 7). The relative α E fibrinogen levels were higher in ICU patients with COVID-19 than in healthy controls, while relative γ' fibrinogen levels were lower. After diagnosis of thrombosis, only the functional fibrinogen levels were higher in ICU patients with COVID-19 and thrombosis than in those without, while no differences were observed in the other fibrinogen variants. Conclusion  Our results show that severe COVID-19 is associated with increased levels of α E fibrinogen and decreased relative levels of γ' fibrinogen, which may be a cause or consequence of severe disease, but this is not associated with the development of thrombosis.</p

Predictors of virological failure in HIV-1-infected patients switching to dolutegravir maintenance monotherapy

Objectives: The Dolutegravir Monotherapy for HIV (DOMONO; NCT02401828) study showed that maintenance monotherapy with dolutegravir (DTG) is associated with virological failure (VF) and leads to DTG resistance and as a result should not be used. However, data on clinical and virological factors associated with VF during DTG monotherapy are lacking. We identified factors associated with VF during DTG monotherapy. Methods: A randomized trial was carried out in which patients on combination antiretroviral therapy (cART) with an HIV-1 RNA zenith < 100 000 copies/mL and a CD4 T-cell nadir ≥ 200 cells/μL, who had never experienced VF, switched to DTG monotherapy. Clinical and virological factors were compared between patients with and without VF, using univariate analyses. Results: Eight of the 95 patients developed VF during DTG monotherapy. A total of 78 participants had reached week 48 when the study was discontinued. The median CD4 T-cell nadir was lower in patients with VF than in patients without VF [260 (interquartile range (IQR) 223–320) versus 380 (IQR 290–520) cells/μL, respectively; P = 0.011]. Patients with VF had a longer time between HIV diagnosis and cART initiation than those without VF [median 49 (IQR 27–64) versus 15 (IQR 1–38) months, respectively; P = 0.015]. The median total peripheral blood mononuclear cell (PBMC) HIV DNA copy number was higher in patients with VF than in those without VF [417 (range 85–4151) versus 147 (range 16–4132) copies/106 PBMCs, respectively; P = 0.022]. Conclusions: A lower CD4 nadir, a longer time between HIV diagnosis and cART initiation, and a higher HIV DNA copy number at the time of DTG monotherapy initiation were associated with VF. While there clearly is no future role for DTG monotherapy, ongoing and future studies on the efficacy of maintenance dual therapy (e.g. DTG lamivudine) may have to take these variables into account in their study design and analysis

Predictors of virological failure in HIV-1-infected patients switching to dolutegravir maintenance monotherapy

Objectives: The Dolutegravir Monotherapy for HIV (DOMONO; NCT02401828) study showed that maintenance monotherapy with dolutegravir (DTG) is associated with virological failure (VF) and leads to DTG resistance and as a result should not be used. However, data on clinical and virological factors associated with VF during DTG monotherapy are lacking. We identified factors associated with VF during DTG monotherapy. Methods: A randomized trial was carried out in which patients on combination antiretroviral therapy (cART) with an HIV-1 RNA zenith < 100 000 copies/mL and a CD4 T-cell nadir ≥ 200 cells/μL, who had never experienced VF, switched to DTG monotherapy. Clinical and virological factors were compared between patients with and without VF, using univariate analyses. Results: Eight of the 95 patients developed VF during DTG monotherapy. A total of 78 participants had reached week 48 when the study was discontinued. The median CD4 T-cell nadir was lower in patients with VF than in patients without VF [260 (interquartile range (IQR) 223–320) versus 380 (IQR 290–520) cells/μL, respectively; P = 0.011]. Patients with VF had a longer time between HIV diagnosis and cART initiation than those without VF [median 49 (IQR 27–64) versus 15 (IQR 1–38) months, respectively; P = 0.015]. The median total peripheral blood mononuclear cell (PBMC) HIV DNA copy number was higher in patients with VF than in those without VF [417 (range 85–4151) versus 147 (range 16–4132) copies/106 PBMCs, respectively; P = 0.022]. Conclusions: A lower CD4 nadir, a longer time between HIV diagnosis and cART initiation, and a higher HIV DNA copy number at the time of DTG monotherapy initiation were associated with VF. While there clearly is no future role for DTG monotherapy, ongoing and future studies on the efficacy of maintenance dual therapy (e.g. DTG lamivudine) may have to take these variables into account in their study design and analysis