Olfactory and gustatory dysfunctions in COVID-19 outpatients: A prospective cohort study.

OBJECTIVES: To describe the characteristics, evolution and risk factors for long-term persistence of olfactory and gustatory dysfunctions (OGD) in COVID-19 outpatients. PATIENTS AND METHODS: We conducted a prospective study in SARS-CoV-2 infected outpatients with OGD. Weekly phone interviews were set up starting from COVID-19 onset symptoms and over the course of 60 days, using standardized questionnaires that included a detailed description of general symptoms and OGD. The primary outcome was the proportion of patients with complete recovery of OGD at D30. Rate and time to recovery of OGD, as well as risk factors for late recovery (>30 days), were evaluated using Cox regression models. RESULTS: Ninety-eight outpatients were included. The median time to onset of OGD after first COVID-19 symptoms was 2 days (IQR 0-4). The 30-day recovery rate from OGD was 67.5% (95% CI 57.1-75.4) and the estimated median time of OGD recovery was 20 days (95% CI 13-26). Risk factors for late recovery of OGD were a complete loss of smell or taste at diagnosis (HR=0.26, 95% CI 0.12-0.56, P=0.0005) and age over 40 years (HR=0.56, 95% CI 0.36-0.89, P=0.01). CONCLUSIONS: COVID-19 patients with complete loss of smell or taste and over age 40 are more likely to develop persistent OGD and should rapidly receive sensorial rehabilitation.

Long-term follow-up of HIV-infected patients on dolutegravir monotherapy.

BACKGROUND: In recent years, dolutegravir monotherapy has been explored as a drug-reduced regimen for HIV patients. METHODS: This was a retrospective observational study, including patients virologically suppressed for ≥6 months, without previous virological failure (VF) under integrase inhibitors (INIs), who had been switched to dolutegravir monotherapy (50 mg/day). The primary aim was to report the proportion of VF at week 48 (W48) and week 96 (W96) of dolutegravir monotherapy. The evolution from baseline to W48 of residual viraemia on ultra-deep sequencing and HIV DNA was also evaluated. RESULTS: Sixty-one patients were included. Prior to switching to dolutegravir monotherapy, they had a median (IQR) of 15.4 (6.5-19.9) years of antiretroviral exposure, 5.8 (3.2-10.3) years of viral suppression and 687 (461-848) CD4+ cells/mm3. They remained on dolutegravir monotherapy for a median (IQR) of 100 (29-148) weeks. Forty-two out of 61 patients (68.9%) reached W48 and 32 out of 61 patients (52.5%) reached W96. VF occurred in three patients, with the emergence of INI resistance. VF occurred before W24 and in patients pre-exposed to INIs. At W48, the probability of VF (Kaplan-Meier analysis) was 5.6% (95% CI = 1.8%-16.4%). The same result was obtained at W96. Detectable residual viraemia did not increase and median HIV DNA did not change significantly (2.4 log/106 cells at baseline and 2.3 log/106 cells at W48). Dolutegravir plasma concentration was above the IC90 in 41/41 samples, from 22 patients. CONCLUSIONS: Long-term follow-up showed a low risk of VF under dolutegravir monotherapy, in a selected population of patients with previous long-term virological suppression and low HIV reservoir.

Dynamics of drug resistance-associated mutations in HIV-1 DNA reverse transcriptase sequence during effective ART.

Objectives: To investigate the dynamics of HIV-1 variants archived in cells harbouring drug resistance-associated mutations (DRAMs) to lamivudine/emtricitabine, etravirine and rilpivirine in patients under effective ART free from selective pressure on these DRAMs, in order to assess the possibility of recycling molecules with resistance history. Patients and methods: We studied 25 patients with at least one DRAM to lamivudine/emtricitabine, etravirine and/or rilpivirine identified on an RNA sequence in their history and with virological control for at least 5 years under a regimen excluding all drugs from the resistant class. Longitudinal ultra-deep sequencing (UDS) and Sanger sequencing of the reverse transcriptase region were performed on cell-associated HIV-1 DNA samples taken over the 5 years of follow-up. Results: Viral variants harbouring the analysed DRAMs were no longer detected by UDS over the 5 years in 72% of patients, with viruses susceptible to the molecules of interest found after 5 years in 80% of patients with UDS and in 88% of patients with Sanger. Residual viraemia with <50 copies/mL was detected in 52% of patients. The median HIV DNA level remained stable (2.4 at baseline versus 2.1 log10 copies/106 cells 5 years later). Conclusions: These results show a clear trend towards clearance of archived DRAMs to reverse transcriptase inhibitors in cell-associated HIV-1 DNA after a long period of virological control, free from therapeutic selective pressure on these DRAMs, reflecting probable residual replication in some reservoirs of the fittest viruses and leading to persistent evolution of the archived HIV-1 DNA resistance profile.

Efficacy of raltegravir switching strategies in HIV-infected patients with suppressed viraemia according to the genotypic sensitivity score.

BACKGROUND AND PURPOSE: The lack of antiretroviral (ARV) backbone activity associated with raltegravir has been proposed as the main explanation for virological relapse observed in patients with undetectable viraemia who are switched from a ritonavir-boosted protease inhibitor (PI) to raltegravir. However ARV activity remains difficult to assess in this context. The aim of our study was to precisely assess the ARV backbone activity in patients with undetectable viraemia who underwent raltegravir switching strategies and to evaluate the efficacy of such switching strategies based on the genotypic sensitivity score (GSS). METHODS: Patients with a plasma human immunodeficiency virus type 1 (HIV-1) RNA level of <50 copies/mL on a stable two ARV-class regimen were enrolled if they switched one of their ARV drugs to raltegravir 400 mg twice daily. The GSS was calculated using a genotyping test performed on the HIV-1 RNA of the last plasma measurement with a HIV-1 RNA level of >50 copies/mL before the switch and on the results of all previous genotyping tests. The primary endpoint was the proportion of patients with a plasma HIV-1 RNA level of <50 copies/mL at week 24. RESULTS: Fifty-six patients were enrolled in this study. The proportion of patients with a plasma HIV-1 RNA level of <50 copies/mL at week 24 was 92.9 % (range 83.0-97.2 %) in the intent-to-treat analysis and 98.1 % (90.0-99.7 %) in per-protocol analysis. When the backbone was fully active, the proportion was 100.0 % (86.7-100.0 %) at week 24 and week 48 in the per-protocol analysis. We observed a decrease in plasma total cholesterol and triglycerides of -12.7 % (p = 0.005) and -26.5 % (p = 0.001), respectively. CONCLUSIONS: Raltegravir switching strategies are effective when the associated backbone is fully active according to the GSS. In the context of undetectable viraemia, where ARV activity remains difficult to assess, the determination of the GSS requires the entire ARV history of the patient and all previous HIV-RNA genotyping test results.

Switch from etravirine twice daily to once daily in non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-infected patients with suppressed viremia: the Monetra study.

BACKGROUND: Etravirine (ETR) is recommended as twice-daily dosing in pretreated patients. There are no data regarding the use of ETR once daily in HIV-experienced patients with prior resistance to first-generation non-nucleoside reverse transcripase inhibitors (NNRTIs). OBJECTIVES: To evaluate the capacity of once-daily ETR to maintain suppressed viremia over 48 weeks after switching from ETR twice daily in NNRTI-experienced patients. METHODS: In this pilot open-label study, patients with plasma viral load (pVL) <50 copies/mL on a stable ETR 200 mg bid regimen were enrolled to switch to ETR 400 mg qd and followed up over 48 weeks. The primary endpoint was the proportion of patients with pVL <50 copies/mL at week 24. Secondary endpoints included the rate of pVL< 50 copies/mL at week 48, ETR pharmacokinetic parameters, and tolerability and resistance profile. RESULTS: Twenty-four patients were included. They had extensive antiretroviral treatment for a median of 14 years (range, 1-19). All except for 2 had prior resistance to NNRTIs. Seven patients discontinued ETR once daily prior to week 48 for virological failure (3), protocol deviation (3), and side effects (1). At week 24, 95% of patients maintained pVL< 50 copies/mL (95% CI, 78.4-99.7) and 85% at week 48 (95%CI, 65.6-95.8). Two of the 3 patients with virological failure had ETR resistance mutations prior to initiation. The median ETR C(trough) level remained stable after switching from twice daily 515 ng/mL (340-758) to once daily 422 ng/mL (264-655). CONCLUSION: These results suggest that ETR is effective as a once-daily regimen in patients with prior NNRTI experience when HIV is sensitive to ETR. The stability of C(trough) concentrations on a once-daily regimen confirms the once-daily profile of the drug in experienced patients.

[The Nadis cohort: 6236 HIV-infected patients followed up in French university hospitals]. / Cohorte Nadis: 6236 patients séropositifs suivis dans des CHU de France.

OBJECTIVE: The Nadis electronic medical patient record allows real time constitution of a database including the clinical, therapeutic, biological, and epidemiological features of HIV-positive patients. METHODS: Data concerning HIV-infected patients followed-up in 6 French University Hospitals was collected. Data quality was assessed on a regular basis in each center. RESULTS: The 6 first University hospitals using Nadis agreed to group their data on March 15, 2004, concerning 6236 patients having consulted at least once in the previous year. Among these, 29% were female patients, 80% were under treatment on March 15, 2004, 9% were off treatment, 29% were co-infected by hepatitis B or C virus, 57% had an undetectable viral load, 15% of the treated patients were in a worrying immunovirological situation, 358 were diagnosed HIV-positive in 2003. 35% of these "new patients" were women, the mode of infection was sexual in 80%, 45% were under treatment on March 15, 04. This recent data allowed us to have an accurate assessment of this population's management in 2004.

Persistent low viral load on antiretroviral therapy is associated with T cell-mediated control of HIV replication.

BACKGROUND: It is unclear how stable low-level viral replication and CD4 cell numbers can be maintained under highly active antiretroviral therapy (HAART). This study was designed to analyse whether HIV-specific responses in stable partially controlled patients during antiretroviral therapy (ART) differ from those observed in complete HAART failure and whether they contribute to the control of viral load (VL). METHODS: Three groups of patients were selected according to plasma HIV RNA levels during 18 months of ART: persistently low VL (LoVL; HIV RNA <10,000 copies/ml; n = 28), undetectable VL (UnVL; HIV RNA <200 copies/ml; n = 29) and high VL (HiVL; HIV RNA >10,000 copies/ml; n = 14). T-cell responses were studied using lymphoproliferative and interferon (IFN)-gamma-ELISpot assays against HIV-p24, -gp160, recall antigens, and 15 pools of HIV-(Gag + RT) peptides. RESULTS: Frequencies of IFN-gamma-producing CD4 T cells against HIV-p24 were higher in LoVL than in UnVL or HiVL groups [median, 131, 47 and 23 spot-forming cells (SFC)/1 x 10 peripheral blood mononuclear cells (PBMC), respectively; P = 0.012 and P = 0.047]. Lymphoproliferative responses to HIV-p24 and recall antigens were similar in LoVL and UnVL groups but lower in HiVL (P = 0.004). Frequencies of HIV-specific CD8 T cells were higher in LoVL than in UnVL (1340 versus 410 SFC/1 x 10 PBMC; P = 0.001). They correlated negatively with VL in the LoVL and HiVL (r, -0.393, P = 0.039 and r, -0.643, P = 0.024, respectively) and positively correlated with anti-HIV CD4 cell frequencies in the LoVL group only (r, 0.420; P = 0.026). CONCLUSION: Persistently low viral replication (<10,000 copies/ml) during ART stimulates high frequencies of HIV-specific CD4 and CD8 T cells compared to full virus suppression or complete ART failure. The association of high anti-HIV activity with large numbers of HIV-specific CD8 T cells contribute to the control of viral replication.

[NADIS 2000, development of an electronic medical record for patients infected by HIV, HBV and HCV]. / NADIS 2000, développement d'un dossier médical informatisé pour les patients infectés par VIH, VHB et VHC.

OBJECTIVE: to develop an electronic medical record for patients living with HIV, HBV or HCV in order to improve their management, facilitate communication between all the caregivers, and to create a useful medical database for research and assessments. This project (NADIS 2000) involved 6 centres of Infectious Diseases in France in partnership with Fédialis Médica (subsidiary of the GSK group in France). METHODS: A specifications sheets was drawn-up by a piloting Committee regrouping the various correspondents in each centre and a computer expert representing Fédialis Médica. A Scientific and Development committee regrouped the heads of departments of each centre and the representatives from Fédialis Médica and GSK and was charged with defining the general concept of the project and guaranteeing the scientific and clinical aspects. RESULTS: NADIS 2000 version 1.0 was activated in the departments of infectious diseases in Nice and Toulouse in November 2000 and in others Units at the end of 2001. NADIS 2000 permitted real-time use by the physicians in the Outpatients and Day-care Units and was easily handled by all the practitioners. Its use was eased by the principles clearly defined before its application (department project, progressive but exhaustive use), an intuitive interface simulating a consultation, and functions proposing direct benefits for the physicians (graphical visualization of the biological variables, printing of prescriptions and letters). CONCLUSION: The activation and input methods of NADIS 2000 are user friendly and the physicians find it rapidly easy to use. New functional aspects are being developed as well as its use in other hospital departments.

Assessment of hypothalamic-pituitary-adrenal axis function after corticosteroid therapy in inflammatory bowel disease.

OBJECTIVES: In patients with inflammatory bowel disease (IBD), little is known about the effect of long term corticosteroid therapy (CT) on the hypothalamic-pituitary-adrenal (HPA) axis function. Our aim was to assess HPA axis function in IBD, before the end of CT, during the tapering phase. METHODS: HPA axis function was assessed with cortisol (ng/ml) measurement before (T0) (normal > 100) and 60 min (normal > 210) after 0.25 mg tetracosactide (Synacthen immédiat) injection (T60) in 55 consecutive cases of IBD attacks. Abnormal response was defined as a T60 <210. The attacks were separated into two groups according to the result of the Synacthen test (ST). RESULTS: In all, 36 of 55 ST were abnormal. The time for recovery normal HPA axis function was 7.2+/-1.3 months. Duration of disease since onset, past history of surgical or immunosuppressive treatment, severity and extension of the attack, need for surgical or immunosuppressive treatment, total cumulative and mean daily corticosteroid dose, total duration of CT, and steroid dose at the time of ST were not significantly different in the two groups. In multivariate analysis a past history of CT was predictive of abnormal ST (OR = 8.4, 95% CI = 2.2-31.5, p = 0.0009). Among patients with a past history of CT, the time (months) elapsed between the last course of CT was significantly longer in those with normal ST than in those with abnormal ST (45.5+/-13.5 vs 15.4+/-6.0; p = 0.02), and in multivariate analysis a duration free of CT < 15 months was predictive of abnormal ST (OR = 15.00, CI = 1.23-183.00, p = 0.03). CONCLUSIONS: In all, 65% of the ST were abnormal. These results suggest that ST should be performed before corticosteroid withdrawal, especially in patients with recent past history of CT.

Resistance profile and cross-resistance of HIV-1 among patients failing a non-nucleoside reverse transcriptase inhibitor-containing regimen.

The objectives were to determine the resistance profile and the rate of cross-resistance in HIV-1 infected patients failing an efavirenz or a nevirapine or a nevirapine then efavirenz containing regimens, and to investigate if zidovudine and more generally thymidine analog nucleosides lead to a particular genotypic pattern in nevirapine failing patients. A study was conducted in 104 patients with virological rebound to a non-nucleoside reverse transcriptase inhibitors (NNRTI) regimen (efavirenz n = 39, nevirapine n = 46 and nevirapine then efavirenz n = 19). Genotypic resistance testing was carried out of detectable plasma HIV-1 RNA (> 200 copies/ml). Among the 104 patients studied, only two patients failed to respond to the nevirapine regimen without selection of a NNRTI resistance mutation. All patients failing an efavirenz regimen harboured mutations conferring cross-resistance to nevirapine (K103N, Y188L, G190S). Among patients failing the nevirapine regimen and presenting with NNRTI mutations, 35 (80%) harboured mutations conferring cross-resistance to efavirenz (K101E, K103N, Y188L) and 9 (20%) harboured mutations conferring resistance to nevirapine alone (V106A and Y181C). In patients failing nevirapine then efavirenz therapy, all NNRTI resistance profile led to cross-resistance to all available NNRTIs. Among patients receiving nevirapine, the selection of mutations associated with a cross-resistance to efavirenz was more frequent statistically when a thymidine nucleoside analog (zidovudine or stavudine) was used in the regimen (P = 0.02). In conclusion, 100% of patients developed cross-resistance to nevirapine and efavirenz after treatment by efavirenz and 80% after treatment by nevirapine. The use of a thymidine analog concomitantly with nevirapine leads to the preferential selection of cross-resistance NNRTI mutations.

[Epidemiological features and incidence trends of primary cerebral lymphomas observed in 80 HIV-infected patients from 1983 to 1999]. / Caractéristiques épidémiologiques et évolution de l'incidence des lymphomes cérébraux primitifs observés chez 80 patients infectés par le VIH entre 1983 et 1999.

OBJECTIVE: To describe the epidemiological characteristics of primary central nervous system lymphoma (PCNSL) and the evolution of the incidence of this lymphoma in HIV-infected patients with a more than 17-year follow-up. RESULTS: Eighty cases of PCNSL were analyzed from a data base of 2,263 AIDS subjects followed from 1983 to 1999 (3.5% of the patients with AIDS). At the time of diagnosis, PCNSL was the first AIDS defining event in 36% of the cases, median CD4 count was 9/mm3 (0-134); 82% of the patients were given antiretroviral therapy (HAART = 0). Only eight cases of PCNSL were observed after 1996 (median HIV RNA level: 250,000 copies/mL (24,000-1,500,000)). The incidence was 39 per 100 patients-year in 1991 and decreased to 1.9 in 1999. At the end of the study, 78 patients had died (98%). The median survival was one month before 1996 ([0-27], n = 72), and was ten months after ([0-44], n = 8). Two patients were still alive 38 and 44 months after diagnosis. After 1996, survival was increased in patients with good response to antiretroviral treatment and in patients with high CD4 count at the moment of diagnosis. CONCLUSION: After the introduction of HAART (1996), the incidence of PCNSL has decreased drastically and survival was increased.

Analysis of factors predictive of survival based on 49 patients with systemic Wegener's granulomatosis and prospective follow-up.

OBJECTIVES: This prospective study attempted to determine factors predictive of survival in systemic Wegener's granulomatosis (WG) based on 49 patients. Patients and methods. All patients had previously untreated systemic WG. Treatment was with oral or pulse cyclophosphamide plus corticosteroids. Univariate and multivariate analyses of survival were performed using 13 parameters evaluated at diagnosis. RESULTS: The mortality rate was 37% during a mean follow-up period of 1.9 yr. Among the 13 parameters evaluated, univariate analysis selected the following factors as predictors of a poor outcome: serum creatinine > or =18.1 mg/dl, age > or =57 yr, and erythrocyte sedimentation rate (ESR) > or =90 mm/1st h. The absence of ear, nose and throat (ENT) involvement also tended to predict a greater risk of mortality. Glomerulonephritis, when present and regardless of creatininaemia, and pulmonary involvement had no significant effect. Multivariate analysis retained serum creatinine > or =18.1 mg/dl and age > or =57 yr as significant predictors of poor prognosis. CONCLUSIONS: Our results suggest that impaired renal function and older age are independent factors predicting poor outcome in WG. ESR proved to be a good marker of disease severity. Conversely, univariate analysis indicated that patients with ENT involvement tended to have a better outcome, suggesting a more benign evolution of granulomatous disease compared with more aggressive vasculitis.

Outcome of kidney transplant recipients with previous human herpesvirus-8 infection.

BACKGROUND: The consequences of a prior human herpesvirus-8 (HHV-8) infection in kidney-transplant recipients are still partially unknown. The aim of this monocentric study was to determine the prevalence of HHV-8-seropositive patients at the time of transplantation and to identify the main clinical events of these HHV-8+ recipients. METHODS: From January 1, 1990 to December 31, 1996, antibodies to HHV-8 latent nuclear antigen were detected by indirect immunofluorescent method in serum samples collected just before kidney transplantation from 400 consecutive patients. Conventional double or triple immunosuppressive treatment was prescribed. For the group of HHV-8+ recipients, data including death rate, graft survival, and occurrence of Kaposi's sarcoma (KS) were retrospectively collected until December 31, 1998. Cofactors associated with KS were studied in univariate and multivariate analyses using a Cox model. RESULTS: Thirty-two patients (8%) had antibodies to HHV-8 in their sera at the time of transplantation. Among these 32, 3 years after transplantation, graft survival was 72%, and KS prevalence was 28% (KS incidence: 8.2/yr/100 HHV-8+ recipients). Multivariate analysis identified bacterial and/or Pneumocystis carinii infection (odds ratio: 8.6; P=0.019) and female gender (odds ratio: 5.34; P=0.047) as factors associated with KS. No KS was observed in patients without anti-HHV-8 antibodies at the time of transplantation. CONCLUSIONS: The low graft survival and the high prevalence of KS within the studied population of HHV-8+ transplant recipients are strong arguments for systematic screening of HHV-8 serologic features before transplantation, especially in patients of African origin. HHV-8+ transplant recipients should be closely monitored to severe infections.

Impact of highly active antiretroviral therapy on onset of Mycobacterium avium complex infection and cytomegalovirus disease in patients with AIDS.

OBJECTIVES: To assess the impact of highly active antiretroviral therapy (HAART) on the onset of first disseminated Mycobacterium avium complex (MAC) infection and first cytomegalovirus (CMV) disease episode in HIV-infected at-risk patients. METHODS: The incidence of the two infections occurring in at-risk patients was calculated for two periods (January 1995-June 1996 and July 1996-December 1997) using the database of the HIV-infected patients followed in the Infectious Diseases Department at the Pitié-Salpêtrière Hospital in Paris. HAART was progressively introduced in late June 1996 in France. RESULTS: A total of 91 first disseminated MAC infections and 124 first CMV disease episodes were recorded. The incidence of first disseminated MAC infections fell from 13.4 per 100 person-years in the first 18-month period to 2.6 per 100 person-years in the second 18-month period. Similarly, the incidence of first CMV disease episodes fell from 20.9 to 3.5 per 100 person-years. Fourteen patients on HAART developed a first MAC infection, 12 (85.7%) within 2 months of starting HAART. Nineteen patients on HAART had a first CMV disease episode, 10 (52.6%) within 2 months of starting HAART. CONCLUSIONS: HAART led to a five-fold decrease in the incidence of first disseminated MAC infections and a six-fold decrease in first CMV disease episodes, although patients remain vulnerable to both diseases for approximately 2 months after starting HAART.

[Multicenter evaluation on different analyzers of three methods for direct HDL-cholesterol assay]. / Evaluation multicentrique sur différents automates d'analyses de trois méthodes de dosage direct du cholestérol-HDL.

Most frequently, in routine laboratories, C-HDL is measured in the supernatant after precipitation of apolipoprotein B-containing lipoproteins by the sodium phosphotungstate/magnesium chloride reagent (PTA). This method involves precipitation, centrifugation and decantation steps which prevent full automation of the measurement and decrease the accuracy of the results. Recently, three direct assays for C-HDL including alpha-cyclodextrin sulphate (alpha-CD), polyanions/detergents (PA-D) or antibodies anti-beta-lipoproteins (AC) have been commercialized, in which all steps are fully managed by automated analyzers. These new methods have been compared to the conventional procedure (PTA), in multicenter studies among six laboratories using different analyzers. The C-HDL values measured by the alpha-CD and PA-D assays correlated well with those of the PTA method (r > 0.98), on most of the analyzers. With the AC assay, only the results obtained with the Hitachi 717 analyzer were correlated with C-HDL values of the PTA method. The linearity and specificity studies were evaluated in the laboratory A on a Kone Specific analyzer. The alpha-CD and PA-D assays were linear for C-HDL values from 0 to 5.56 mmol/l, as observed by increasing amounts of HDL2 + HDL3 or serum without lipoprotein isolated by ultracentrifugation. The specificity of these two methods was evaluated simultaneously, by adding various amounts of lipoproteins isolated by sequential ultracentrifugation. No interference was observed when adding chylomicrons up to 13.4 mmol/l of triglycerides for both methods. Inversely, increased C-HDL values were observed with added VLDL from 6 mmol/l of triglycerides for the PA-D assay and from 8 mmol/l for the alpha-CD assay. No interference was observed with added LDL up to 11.5 mmol/l of C-LDL for the alpha-CD assay and up to 6.7 mmol/l for the PA-D assay. In conclusion, the present multicenter evaluation demonstrates that the new procedures for the direct automation of C-HDL are easy and accurate and most of them correlated well with the classical precipitation method. In addition the study provides arguments for a choice between the different direct C-HDL methods.

Elevated plasma fibrinogen and increased fibrin turnover among healthy women who both smoke and use low-dose oral contraceptives--a preliminary report.

Among users of low-dose oral contraceptives (OC), cardiovascular diseases occur mainly in smokers. The mechanisms by which OC and smoking increase the risk for arterial thrombotic risk have not been adequately explained. Epidemiological evidence suggests that changes in blood coagulation and fibrinolysis may play an important role as determinants of thrombotic events. Therefore, we have investigated the associations of OC and smoking with haemostatic variables among 194 premenopausal healthy women. Fourty women were current users of low-dose OC and 62 women were smokers. After adjustment for age and body mass index, mean values of factor XIIa, factor VII activity and antigen, fibrinogen, D-dimer, global fibrinolytic capacity were significantly higher in OC users than in non-users. Mean levels of PAI activity and t-PA antigen were significantly lower in OC users than in non-users. Smokers had significantly higher mean values of fibrinogen than non-smokers. Two-way analysis of variance showed that the differences in mean levels of fibrinogen and D-dimer between OC users and non users were restricted to smokers. The positive and significant interactions between OC use and smoking in their effects on haemostatic variables were consistent with respect to age and type of OC. These preliminary data suggest that elevated plasma levels of fibrinogen and intravascular fibrin deposition may play a role in the pathogenesis of arterial thrombotic disease among women who are both low-dose OC users and smokers.

Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial.

Postmenopausal hormone replacement therapy is associated with a reduction in the incidence of coronary heart disease. However, inconclusive results have been reported with respect to the risk of stroke, and recent studies consistently showed an increased risk of venous thromboembolism in postmenopausal women using oral estrogen. There are surprisingly few interventional studies to assess the true effects of estrogen-progestin regimens on blood coagulation and fibrinolysis, and the impact of the route of estrogen administration on hemostasis has not been well documented. Therefore, we investigated the effects of oral and transdermal estradiol/progesterone replacement therapy on hemostatic variables. Forty-five healthy postmenopausal women, aged 45 to 64 years, were assigned randomly to one of the three following groups: cyclic oral or transdermal estradiol, both combined with progesterone, or no hormonal treatment. Hemostatic variables were assayed at baseline and after a 6-month period. Pairwise differences in the mean change between the three groups were compared using nonparametric tests. Oral but not transdermal estradiol regimen significantly increased the mean value of prothrombin activation peptide (F1 + 2) and decreased mean antithrombin activity compared with no treatment. Differences in fragment F1 + 2 levels between active treatments were significant. The oral estrogen group was associated with a significant decrease in both mean tissue-type plasminogen (t-PA) concentration and plasminogen activator inhibitor (PAI-1) activity and a significant rise in global fibrinolytic capacity (GFC) compared with the two other groups. A transdermal estrogen regimen had no significant effect on PAI-1, t-PA, and GFC levels. There were no significant changes in mean values of fibrinogen, factor VII, von Willebrand factor, protein C, fibrin D-dimer, and plasminogen between and within the three groups. We conclude that oral estrogen/progesterone replacement therapy may result in coagulation activation and increased fibrinolytic potential, whereas opposed transdermal estrogen appears without any substantial effects on hemostasis. Whereas these results may account for an increased risk of venous thromboembolism in users of oral postmenopausal estrogen, they emphasize the potential importance of the route of estrogen administration in prescribing hormone replacement therapy to postmenopausal women, especially to those at high risk of thrombotic disease.

Population correlates of coagulation factor VII. Importance of age, sex, and menopausal status as determinants of activated factor VII.

Factor VII coagulant activity (FVIIc) has been found to be related to cardiovascular risk factors and may be an independent predictor of coronary heart disease (CHD). Whether these associations are due to changes in FVII activation rather than FVII concentration remain unclear. Therefore, we investigated the relationships between activated factor VII (FVIIa) and CHD risk factors in healthy subjects (336 men and 348 women) aged 25 to 64 years. In addition to direct quantitation of FVIIa by use of a recombinant, truncated tissue factor, FVIIc and factor VII antigen (FVII:Ag) levels were measured by standard procedures. There were highly significant correlations between the three techniques of FVII assay (r > + .55). Plasma FVIIc and FVIIa levels increased with age in both sexes, but the rate of rise was significantly greater in women than men. At younger ages, mean values of FVIIc and FVIIa were significantly lower in women than men, whereas at older ages the reverse was observed. After adjustment for age, postmenopausal women had significantly higher mean levels of FVIIc and FVIIa than did premenopausal women. Hormone replacement therapy significantly reversed the rise in FVIIc in postmenopausal women, and a similar trend in FVIIa was also observed. Age-, sex-, and menopause-related changes in FVIIc were partly explained by a higher proportion of fully active FVII molecules, as indicated by significant differences in the FVIIa-to-FVII:Ag ratio. Oral contraceptive use was associated with high FVIIc levels, and this effect was mainly due to an increase in FVII:Ag. Levels of FVIIa were positively correlated with serum cholesterol concentrations in both sexes. There were no strong associations between FVIIa levels and other CHD risk factors, including smoking habits, alcohol consumption, blood pressure, obesity, glucose, triglycerides, and serum lipoprotein(a) concentrations. Multiple regression analysis showed independent effects of age and cholesterol levels on FVIIa in men, whereas age and menopausal status were the main predictors of FVIIa in women. Our results show that FVII activation is associated with CHD risk factors. These findings are consistent with a possible role for FVII in the pathogenesis of CHD. Furthermore, our data suggest that the dramatic rise in CHD incidence in postmenopausal women as well as the cardioprotective effect of estrogen may be mediated through FVII and blood coagulation.