Risk of readmission and death after hospitalization for worsening heart failure: Role of post-discharge follow-up visits in a real-world study from the Grand Est Region of France.

AIMS: Patients who experience hospitalizations due to heart failure (HF) face a significant risk of readmission and mortality. Our objective was to evaluate whether the risk of hospitalization and mortality following discharge from HF hospitalization differed based on adherence to the outpatient follow-up (FU) protocol comprising an appointment with a general practitioner (GP) within 15 days, a cardiologist within 2 months or both (termed combined FU). METHODS AND RESULTS: We studied all adults admitted for a first HF hospitalization from 2016 to 2020 in France's Grand Est region. Association between adherence to outpatient FU and outcomes were assessed with time-dependent survival analysis model. Among 67 476 admitted patients (mean age 80.3 ± 11.3 years, 53% women), 62 156 patients (92.2%) were discharged alive and followed for 723 (317-1276) days. Combined FU within 2 months was used in 21.1% of patients, with lower rates among >85 years, women, and those with higher comorbidity levels (p < 0.0001 for all). Combined FU was associated with a lower 1-year death or rehospitalization (adjusted hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.88-0.94, p < 0.0001) mostly related to lower mortality (adjusted HR 0.65, 95% CI 0.62-0.68, p < 0.0001) whereas HF readmission was higher (adjusted HR 1.19, 95% CI 1.15-1.24, p < 0.0001). When analysing components of combined FU separately, 1-year mortality was more related to cardiologist FU (HR 0.65, 95% CI 0.62-0.67, p < 0.0001), than GP FU (HR 0.87, 95% CI 0.85-0.90, p < 0.0001). CONCLUSION: Combined FU is carried out in a minority of patients following HF hospitalization, yet it is linked to a substantial reduction in 1-year mortality, albeit at the expense of an increase in HF hospitalizations.

Presence of lamivudine or emtricitabine is associated with reduced emergence of nonnucleoside reverse transcriptase inhibitor mutations in an efavirenz-based intermittent antiretroviral treatment regimen.

Efavirenz concentrations were measured in 21 patients during an interruption cycle of the ANRS 106 Window trial. The median efavirenz concentrations in the patients 12 h, 3 days, and 7 days after discontinuation of the drug were 1,962 ng/ml, 416 ng/ml, and 112 ng/ml, respectively. The half-life ranged from 27 to 136 h. No relationship between efavirenz exposure and detection of nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations was demonstrated. Patients who were treated by a lamivudine- or emtricitabine-based regimen had a lower risk of NNRTI mutation selection.

Minor HIV-1 variants with the K103N resistance mutation during intermittent efavirenz-containing antiretroviral therapy and virological failure.

UNLABELLED: The impact of minor drug-resistant variants of the type 1 immunodeficiency virus (HIV-1) on the failure of antiretroviral therapy remains unclear. We have evaluated the importance of detecting minor populations of viruses resistant to non-nucleoside reverse-transcriptase inhibitors (NNRTI) during intermittent antiretroviral therapy, a high-risk context for the emergence of drug-resistant HIV-1. We carried out a longitudinal study on plasma samples taken from 21 patients given efavirenz and enrolled in the intermittent arm of the ANRS 106 trial. Allele-specific real-time PCR was used to detect and quantify minor K103N mutants during off-therapy periods. The concordance with ultra-deep pyrosequencing was assessed for 11 patients. The pharmacokinetics of efavirenz was assayed to determine whether its variability could influence the emergence of K103N mutants. Allele-specific real-time PCR detected K103N mutants in 15 of the 19 analyzable patients at the end of an off-therapy period while direct sequencing detected mutants in only 6 patients. The frequency of K103N mutants was <0.1% in 7 patients by allele-specific real-time PCR without further selection, and >0.1% in 8. It was 0.1%-10% in 6 of these 8 patients. The mutated virus populations of 4 of these 6 patients underwent further selection and treatment failed for 2 of them. The K103N mutant frequency was >10% in the remaining 2, treatment failed for one. The copy numbers of K103N variants quantified by allele-specific real-time PCR and ultra-deep pyrosequencing agreed closely (ρ = 0.89 P<0.0001). The half-life of efavirenz was higher (50.5 hours) in the 8 patients in whom K103N emerged (>0.1%) than in the 11 patients in whom it did not (32 hours) (P = 0.04). Thus ultrasensitive methods could prove more useful than direct sequencing for predicting treatment failure in some patients. However the presence of minor NNRTI-resistant viruses need not always result in virological escape. TRIAL REGISTRATION: ClinicalTrials.gov NCT00122551.

Incidence and risk factors of thrombocytopenia in patients receiving intermittent antiretroviral therapy: a substudy of the ANRS 106-window trial.

BACKGROUND: Incidence and risk factors for thrombocytopenia in patients discontinuing highly active antiretroviral therapy (HAART) have not been fully investigated. METHODS: Well-suppressed patients on HAART were randomized to continuous (CT) or intermittent therapy (IT) for 96 weeks. Incidence of thrombocytopenia (<150 x 10(3) platelets/mm(3)) was assessed and multivariate analysis performed to identify baseline predictors. Correlations were assessed between platelet, CD4, CD8 T-cell counts, and viral load after treatment interruption. RESULTS: Three hundred ninety-one patients were included, with a median baseline platelet count of 243,000/mm(3). The incidence of thrombocytopenia at week 96 was significantly higher in the IT versus the CT arm (25.4% versus 9.8%, respectively, P < 0.001) and median time to thrombocytopenia was 9 weeks. In multivariate analysis, the IT strategy: odds ratio (OR) = 4.1 (2.1-7.9; P < 0.0001), a history of thrombocytopenia: OR = 11.9 (2.4-57.9; P = 0.002), and a low baseline platelet count: OR = 3.4 (2.3-5.1; P < 0.0001) were associated with an increased risk of thrombocytopenia. Also, after treatment interruption, changes from baseline in platelet counts were correlated with changes in CD4 T-cell counts and plasma HIV RNA levels (P < 0.001 for both). CONCLUSIONS: Intermittent therapy is associated with a high incidence of thrombocytopenia, especially among patients with low platelet counts and a history of thrombocytopenia.

Costs of intermittent versus continuous antiretroviral therapy in patients with controlled HIV infection: a substudy of the ANRS 106 Window Trial.

BACKGROUND: Structured treatment interruptions in chronic HIV infection have been explored as a drug-sparing strategy to reduce drug-related adverse events and costs while maintaining CD4 cell counts at a level high enough to prevent the risk of disease progression. OBJECTIVES: To test the hypothesis and put a figure on the reduction in total medical costs, we conducted a cost study analysis in the setting of a randomized open-label study comparing an intermittent to a continuous antiretroviral regimen. PATIENTS AND METHODS: Four hundred three HIV-1-infected adults who were tolerating highly active antiretroviral therapy (HAART), with a nadir CD4 count of 100 cells per microliter or more and a CD4 count above 450 cells per microliter at screening, were randomly assigned to switch to a fixed 8-week off, 8-week on intermittent treatment (IT) or to maintain their current treatment (CT) strategy. The proportions of patients who reached a CD4 cell count below 300 cells per microliter through 96 weeks (primary end point) were not significantly different between arms. Costs were estimated from the viewpoint of the payer over the 96-week study period. Unit costs were provided from the national reimbursement schedules for hospital inpatient and outpatient admissions and ambulatory visits and the national selling price for medications. All analyses were performed on an intention-to-treat basis. RESULTS: Complete cost data were available for 391 patients (197 patients in the IT and 194 in the CT arms). The mean cost in euros (Euro) per patient over the 96 weeks of follow-up (excluding protocol-driven costs) was 9738 in the IT arm vs. 16,162 in the CT arm, a 6424 difference almost entirely due to the difference in HAART cost. Mean protocol-driven costs represented Euro290 in the IT vs. Euro280 in the CT arm. The use of IT achieved a 40% reduction in the total cost of HAART. CONCLUSIONS: Reducing by 40% the cost ofHAART medications in a treatment interruption strategy did not increase the costs related to adverse events or consultations.

HIV-1-resistant strains during 8-week on 8-week off intermittent therapy and their effect on CD4+ T-cell counts and antiviral response.

BACKGROUND: We aimed here to study drug-associated HIV resistance mutations in peripheral blood mononuclear cells (PBMC) and plasma during intermittent therapy. METHODS: A substudy of 86 patients randomized to the intermittent treatment arm (8-week on/8-week off) of the ANRS 106 Window trial. HIV reverse transcriptase and protease genes were sequenced and resistance mutations identified according to the International AIDS Society list. RESULTS: Resistance mutations were detected in PBMC of 27/86 (31%) patients at baseline and 25/72 (35%) patients at week 96. Resistance mutations were detected in plasma of 28/86 (33%), 24/83 (29%) and 33/80 (41%) patients at weeks 8, 40 and 88, respectively. The detection of nucleoside reverse transcriptase inhibitor and protease inhibitor associated resistance mutations in plasma remained stable over time, but there was an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated resistance mutations in patients on an NNRTI-based regimen: 1/33 (3%) versus 7/26 patients (27%) at weeks 8 and 88, respectively (P=0.02). The proportions of patients with plasma HIV RNA levels < or =400 copies/ml after 8 weeks of treatment at weeks 16, 48 and 96 in patients with drug-resistant and wild-type viruses were 93% versus 74% (P=0.04), 96% versus 88% (P=0.43) and 70% versus 84% (P=0.13), respectively. Patients with drug-resistant virus had a lower CD4+ T-cell decrease from baseline at weeks 40 and 88 as compared to patients with wild-type virus (P=0.05 and 0.002, respectively). CONCLUSIONS: NNRTI-associated resistance mutations increased over time in plasma of patients who were given NNRTIs. Drug-associated HIV resistance mutations did not seem to impair short-term antiviral response and might be associated with reduced CD4' T-cell loss during interruptions.

Intermittent antiretroviral therapy in patients with controlled HIV infection.

BACKGROUND: To assess the safety of a drug-sparing treatment regimen in patients with high CD4 cell counts and controlled HIV replication under antiretroviral therapy. METHODS: An open-label, non-inferiority study involving 403 adults with CD4 cell counts of 450 x 10(6) cells/l or greater and plasma HIV-1-RNA levels less than 200 copies/ml, randomly assigned to switch to an 8-week off, 8-week on regimen or to continue their antiretroviral regimen. The primary endpoint was the proportion of patients reaching a confirmed CD4 cell count less than 300 x 10(6) cells/l. RESULTS: Over 96 weeks, the proportion of patients meeting this endpoint was non-inferior in the intermittent group (3.6 versus 1.5%, upper bound of the 95% confidence interval of the difference 5.6%). No AIDS-defining event and two non-HIV-related deaths (intermittent arm) were recorded. The median decrease from baseline in the CD4 cell count was greater in the intermittent arm (-155 versus -8 x 10(6) cells/l, P < 0.0001). Minor HIV-related events, mainly lymphadenopathy and mucosal candidiasis, were more frequent in the intermittent group (14 versus 7%, P = 0.04) as were thrombocytopenia. The incidence of grade 3-4 non-HIV-related events and laboratory abnormalities were not statistically different between the groups. At week 96, the proportion of patients with plasma HIV-1-RNA levels less than 400 copies/ml were 81 and 90% in the intermittent (8 weeks after treatment resumption) and continuous groups (P = 0.02), respectively, with similar patterns of HIV resistance genotypes. CONCLUSION: Despite some limitations, an 8-week off and on intermittent treatment regimen appeared clinically safe over 96 weeks while sparing half of the drug exposure.

Experience using MedDRA for global events coding in HIV clinical trials.

OBJECTIVES: To assess the feasibility of coding with MedDRA, the Medical Dictionary for Regulatory Activities, not only serious adverse events required for notification but also all other events usually reported in HIV clinical trials. To develop an approach for MedDRA implementation within an institutional research unit that contributes to an efficient, concise and reproducible event coding. To evaluate the impact of the maintenance and the versioning of this new medical terminology. METHODS: MedDRA versions 3.0 and 5.0 were used for coding hundreds of events reported through two HIV clinical trials. The implementation of MedDRA consisted in the setup of a training program, guidelines to clinical investigators, coding rules and medical validation process. MedDRA version 6.1 was applied to the coding made with the MedDRA version 5.0 in order to identify the assignments affected by the new version and to determine the impact of versioning. RESULTS: Coding with MedDRA all types of events in HIV clinical trials was feasible even though coders experienced some difficulties due mainly to the lack of precision in the investigator verbatim and the high specificity and sensitivity of MedDRA. The addition of appropriate tools to support the use of MedDRA improved significantly the coding of all types of events in HIV clinical trials. The impact of MedDRA versioning was limited and did not result in significant issues. The global implementation process of MedDRA required important resources in terms of qualified personnel, organisation and maintenance. CONCLUSIONS: Guidelines for investigators, coding rules and medical validation appeared to be mandatory for a successful implementation of MedDRA. The use of MedDRA, with the addition of the mentioned support tools, should ensure coding consistency and facilitate the clinical and tolerance analyses and meta-analyses in clinical trials.