High-dose Prophylaxis Research Articles

History of prophylaxis

History of prophylaxis

Toward a prophylaxis against fetal and neonatal alloimmune thrombocytopenia: induction of antibody‐mediated immune suppression and prevention of severe clinical complications in a murine model

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a severe bleeding disorder caused by maternal antibody-mediated destruction of fetal or neonatal platelets (PLTs). Results from our recent large screening study suggest that the pathophysiology of FNAIT is more similar to hemolytic disease of the fetus and newborn (HDFN) than previously thought. Immunization against HPA-1a might therefore be preventable by a prophylactic regimen of inducing antibody-mediated immune suppression (AMIS), which has been documented to be a useful prophylaxis against HDFN. This preclinical proof-of-concept study investigated whether passive administration of anti-β3 integrin could induce AMIS and thereby prevent clinical complications of FNAIT. A murine model of FNAIT using β3 integrin (GPIIIa)-deficient (β3-/-) mice was employed for this study. AMIS in β3-/- mice was induced by intravenous administration of human anti-HPA-1a immunoglobulin G or murine anti-β3 antisera given as prophylaxis after transfusion of HPA-1a-positive human PLTs or murine wild-type PLTs, respectively. AMIS against both human and murine PLT antigens was induced using this prophylactic approach, reducing the amount of maternal PLT antibodies by up to 90%. Neonatal PLT counts were significantly increased and pregnancy outcome was improved in a dose-dependent manner. The incidence of intracranial hemorrhage, miscarriage, and dead-born pups in mice receiving high-dose prophylaxis was reduced to that of normal controls. We also observed that the severity of thrombocytopenia inversely correlated with birth weight. This work conceptually proves that prophylactic administration of PLT antibodies induces AMIS and prevents poor pregnancy outcome in FNAIT.

New Early Prophylaxis Regimen That Avoids Immunological Danger Signals Can Reduce Factor Eight (FVIII) Inhibitor Development Independent From Product Type Used.

Abstract 221 Introduction:Today, the most problematic and costly complication of the treatment of hemophilia A that remains to be overcome is the development of inhibitory antibodies (FVIII inhibitors) to FVIII replacement therapy, particularly in previously untreated patients (PUPs). Aim of the study:The highest risk of developing inhibitors to FVIII is during the first 20 exposure days (EDs). If the patient can be brought through this high risk period without inhibitor development, the subsequent risk is low.We therefore, as a pilot project, developed a prophylaxis regimen for the first 20–50 EDs specifically designed to induce tolerance to the administered FVIII and to minimize inhibitor development. Patients and Methods:Twenty-six consecutive PUPs with severe hemophilia A (<1% FVIII) as they appeared in the centers were treated with a once weekly low dose (250 Units) prophylaxis regimen started as soon as venous access allows without a Port-A-Cath. Thereby immunological danger signals were minimized by avoiding giving first FVIII into a bleed or during an infection, and avoiding surgery during the first 20 EDs. The incidence of inhibitor development in the study group was compared with that in a historical control group of 30 consecutive PUPs with severe hemophilia A treated with a standard joint protection prophylaxis regimen of 40–50 IU/kg FVIII three times a week, starting at or after the first joint or other severe bleed. The new prophylaxis regimen was started after a median of 1 FVIII EDs at a median age of 10.7 months compared to the historical control group were high dose prophylaxis was started later after a median of 30 FVIII on demand EDs at a median age of 19 months (p<0.006). Both plasma-derived and recombinant FVIII concentrates were used in 47% and 53% of the patients respectively. Results:There were no significant differences between the study and control groups in patient related inhibitor risk factors such as ethnicity (all Caucasian), severity of hemophilia (all <1% FVIII), severity of FVIII gene mutation (p<0.0006) and some treatment related factors such as the type of product, age at first exposure, vaccination regimen, need for surgery. However, 14 of 30 subjects (47%) given standard prophylaxis but only 1 of the 26 subjects (3.8%) given the new regimen developed an inhibitor (p=0.0003, odds ratio 0.048, 95% CI: 0.001 to 0.372). Eight subjects given standard prophylaxis but none of those given the new regimen were high responders (p=0.005, odds ratio for high response 0.00, 95% CI: 0.00 to 0.57).Table 1:Treatment related factors for inhibitor development in the study group compared with the control groupControl group (standard prophylaxis regimen) N=30Study group (new prophylaxis regimen) N=26Statistical significanceProduct type:rFVIII (%)16 (53)15 (58)Not significantpdFVIII (%)14 (47)11 (42)Age at start of prophylaxisMedian (months)(n=23)(n=26)Highly significant:Range (months)1910.7p<0.00060.8-870.5-24.5EDs before prophylaxis:MedianHighly significant:range301p<0.00011-infinity0-14Inhibitors (%)14 (47)1 (3.8)Highly significant:p=0.0003Odds ratio =0.048 (95% CI: 0.001 to 0.372)High responders (%)8 (27)0Highly significant:Low responders (%)p=0.0056 (20)1 (3.8)Odds ratio of high response =0.00 (95% CI: 0.00 to 0.57) Conclusion:Our results indicate that early start of prophylaxis associated with minimizing immunological danger signals during the first 20 exposure days with FVIII may reduce the risk of inhibitor formation even in PUPs with a high risk genetic background independent from the FVIII product type used. Once the patients have developed tolerance to FVIII, usually after about 20 to 50 EDs on the low dose regimen, and venous access permitted, prophylaxis might be changed to the normal three times weekly regimen for optimal protection from joint bleedings. These results need to be confirmed in a larger prospective clinical study. Disclosures:Auerswald:Baxter, CSL-Behring and NovoNordisk.: Consultancy, Honoraria, Research Funding. Bidlingmaier:CSL Behring and Bayer : Honoraria. Engl:baxter: Employment. Chehadeh:baxter: Employment. Reipert:baxter: Employment.

10 Year Musculoskeletal Outcomes with Tailored Primary Prophylaxis: The Canadian Hemophilia Prophylaxis Study.

High-dose prophylaxis for severe hemophilia A [25–40 factor (F) VIII Units (u) kg−1 on alternate days] reduces arthropathy, but does so at great cost. (NEJM 2007; 357: 535–544). Less intensive prophylaxis regimens might be cost-effective while reducing the need for indwelling venous access devices and their attendant complications. Tailored prophylaxis starts with FVIII, 50 u kg−1 weekly (Step1). If bleeding frequency is unacceptable (4 joint/soft tissue bleeds or 5 bleeds into a joint on a step of protocol), or if a target joint develops (≥3 bleeds into a single index joint-ankle, elbow or knee) over a consecutive 3-month period the dose of FVIII is escalated to 30 u kg−1 twice weekly (Step 2); a third escalation to 25 u kg−1 on alternate days if bleeding frequency remains unacceptable (Step3).Objectives: To assess the degree of joint damage in the 6 index joints for subjects receiving tailored prophylaxis.Methods: We studied an inception cohort of boys ages 1–2.5 years with severe hemophilia A (<2% FVIII) and no inhibitors treated with tailored prophylaxis. Patients were followed at 6 monthly intervals and parents have kept detailed diaries. Joint damage was measured using a validated physiotherapy joint score and function was assessed using the Child Health Assessment Questionnaire (CHAQ)Results: 54 boys were enrolled from 11 Canadian hemophilia treatment centers. The total follow-up is 3423 patient months (mean 62.2 months, median 54 months and range 5–117 months). 16 (29.6%) boys have been escalated to Step 2 and 14 (25.9%) have escalated to Step 3. 11 of the escalations were due to target joint bleeding. Subjects on study had a mean of 1.4 joint bleeds/patient-year. Physiotherapy Scores Maximum Possible Score Median Observed Range Ankles 56 2 0–20 Elbows 48 0 0–13 Knees 56 0 0–15 All Joints Swelling 18 0 0–4 Muscle Atrophy 18 0 0–3 CHAQ 3 0 0–2 89% of participants were compliant with the primary prophylaxis protocol. Non compliant subjects had the poorest outcomes. No treatment related adverse events have occurred.Conclusion: Tailored primary prophylaxis should be considered as a valid option for long term prophylaxis in young boys with severe hemophilia A.Maximum Possible ScoreMedianObserved RangeAnkles5620–20Elbows4800–13Knees5600–15All JointsSwelling1800–4Muscle Atrophy1800–3CHAQ300–2

Recurrent Antiviral‐Resistant Genital Herpes in an Immunocompetent Patient

Herpes simplex virus type 2 (HSV-2) resistance to antiviral drugs has been described primarily in immunocompromised patients. We report an apparently immunocompetent, human immunodeficiency virus-negative male patient who has experienced repeated HSV-2 genital outbreaks despite receiving antiviral prophylaxis with several different drugs. Several of the HSV-2 genital isolates from this patient have been confirmed as resistant to acyclovir and penciclovir. Antiviral resistance occurred in the setting of long-term prednisone treatment and intermittent acyclovir prophylaxis at suboptimal doses and persisted despite the cessation of oral steroid treatment. The patient's genital herpes outbreaks were not controlled by high-dose prophylaxis with acyclovir, valacyclovir, and famciclovir. Cessation of antiviral prophylaxis resulted in reversion of this patient's HSV-2 isolates to acyclovir and penciclovir sensitivity, although resistant virus reappeared when antiviral prophylaxis was resumed. Transmission of a sensitive HSV-2 strain from this patient to a female sex partner was observed. These observations confirm previous reports that resistance to acyclovir may develop during prophylactic therapy in an otherwise well, immunocompetent patient. These findings support the conclusion that both drug-sensitive and drug-resistant HSV-2 strains established latency in this patient and that both strains are capable of frequent reactivation.

A survey of factor prophylaxis in the Canadian haemophilia A population

High-dose factor prophylaxis, defined as the infusion of 25-40 factor (F) VIII International Units (IU) kg bodyweight (bw)(-1)> or = x 3 per week, started at age 1-2 years of life in boys with severe haemophilia A prevents the development of significant bleed-related arthropathy. However, programmes of prophylaxis are very expensive and venous access is a challenge. To ascertain patterns of prophylaxis in Canada during the period of a global shortage of recombinant FVIII concentrate a survey was conducted in 2001. The response rate was 83% and the survey identified 247 inhibitor-negative haemophilia A cases receiving prophylaxis, defined as the regular administration of FVIII at least once weekly, from 14 Canadian haemophilia treatment centres. The median age of the group identified was 13 years (range: 1-65) and 95% of cases had severe haemophilia A defined by a circulating factor level of <1%. The median FVIII infusion dose was 26 (range: 16-33) IU kg(-1); infusions were administered > or = x 3 per week in 67% of cases. High-dose factor prophylaxis was used most frequently in boys <5 years of age (23 of 28 cases, 82%) as compared with 56% (56 of 100), 66% (40 of 61) and 62% (36 of 58) of males ages 5-12, 13-18 and >18 years. Prophylaxis accounted for 50% of the annual Canadian FVIII consumption and was a major driving force in the 10% increase (=19.3 million FVIII IU) in the FVIII consumption in Canada in the 4-year period 1999-2003. Given the economic implications of increased use of prophylaxis prospective studies are warranted to better define optimal prophylaxis regimens in the haemophilia A population.

Prophylaxis for severe haemophilia: clinical and economical issues.

Patients with severe haemophilia are treated either in case of bleeds only (on demand), or with regular infusions of clotting factor to prevent bleeds (prophylaxis). The introduction of prophylaxis has been hampered by issues of cost and viral safety. In order to compare results and treatment cost of different treatment strategies in adults, three cohorts of patients with severe haemophilia (born 1970-1980) were compared. 106 French patients were treated on demand, 49 Dutch patients were treated with intermediate dose prophylaxis, and 24 Swedish patients were treated with high dose prophylaxis. The annual number of joint bleeds, and the radiological Pettersson score were used to compare outcome, annual clotting factor consumption was used to compare costs. Prophylaxis reduced bleeds and arthropathy: patients treated on demand had a median of 11.5 joint bleeds/year and a median Pettersson score of 16 points, for intermediate dose prophylaxis median bleeds were 2.8 and Pettersson score was 7 points, and for high dose prophylaxis median bleeds were 0.5 joint bleeds and Pettersson score was 4 points. All differences were statistically significant, except the Pettersson scores in both prophylactic regimens. Treatment cost was only increased for high dose prophylaxis: mean clotting factor consumption was 1612 IU kg-1 yr-1 for on demand treatment, 1488 IU kg-1 yr-1 for intermediate dose prophylaxis, and 4012 IU kg-1 yr-1 for high dose prophylaxis. In young adults, the cost of intermediate dose prophylaxis is similar, but outcome is better than for on demand treatment. The cost of high dose prophylaxis is twofold higher, further improving outcome only slightly.

High-dose aprotinin with gentamicin-vancomycin antibiotic prophylaxis increases blood concentrations of creatinine and cystatin C in patients undergoing coronary artery bypass grafting

Both aprotinin and gentamicin-vancomycin antibiotic prophylaxis have been used widely in cardiac surgery to prevent bleeding and infections, respectively. As the drugs are excreted almost entirely by glomerular filtration, we investigated their action on renal function when administered either separately or together. To increase consistency, we measured serum concentrations of creatinine and cystatin C, a new marker of glomerular filtration rate, that many recent studies have shown to be more sensitive than serum creatinine. One hundred patients undergoing coronary artery bypass surgery were allocated randomly to one of four groups: group A received antibiotic prophylaxis with cefamandole and no aprotinin; group B received cefamandole and high-dose aprotinin; group C received antibiotic prophylaxis with gentamicin and vancomycin, but no aprotinin; and group D received both high-dose aprotinin and gentamicin-vancomycin antibiotic prophylaxis. Data from 84 patients, for whom data collection was complete, were analysed. In the first week after operation, mean serum concentrations of cystatin C and creatinine either remained constant or decreased slowly in all groups, except for group D. In group D, both markers increased gradually from postoperative day 2 onwards. The increase in cystatin C was significant on postoperative day 5 (from mean 1.02 (SD 0.11) mg litre-1 before operation to 1.35 (0.32) mg litre-1; P < 0.05), reaching a peak on postoperative day 7 (1.45 (0.35) mg litre-1; P < 0.05), while the increase in creatinine concentration was significant on postoperative day 6 (from 1.05 (0.16) mg dl-1 before operation to 1.29 (0.34) mg dl-1; P < 0.05). We conclude that simultaneous administration of high-dose aprotinin and prophylactic use of gentamicin with vancomycin increased serum concentrations of cystatin C and creatinine in the first postoperative week in patients undergoing cardiac surgery.

Haemophilia prophylaxis in young patients--a long-term follow-up.

To review long-term prophylactic factor treatment in young patients with severe haemophilia A and B, focusing on the orthopaedic and radiological outcome. We received 34 patients with severe haemophilia A (n = 29) and B (n = 5), aged 7-22 years. Age at start of treatment was 1-4.5 years. Dosages of factor concentrate (F VIII and F IX, respectively) were 25-40 IU/kg body weight, three times a week for haemophilia A and twice a week for haemophilia B. The patients had been checked annually over a 5-year period (1990-95). Orthopaedic and radiological joint scores were evaluated according to recommendations by the World Federation of Haemophilia. All results were obtained at the Department for Coagulation Disorders, University of Lund, Malmö University Hospital, Malmö, Sweden. Orthopaedic and radiological joint scores were found to have remained unchanged during follow-up in almost all patients and to be still zero (i.e. no unaffected joints) in 79% (n = 27) of the patients. There is a growing international consensus haemophilic arthropathy can be prevented by administering early high-dose prophylaxis. The results of the present investigation strongly support this opinion.

Determination of the optimal concentration of lithium for the prophylaxis of manic-depressive disorder

A group of 29 bipolar manic-depressives completed a 12-month double-blind cross-over trial of low-dose and high-dose lithium prophylaxis. Twelve patients relapsed, and significantly more of the relapses occurred during the low-dose 6-month phase of the trial. There was a trend for relapse to occur within 2 months of an abrupt drop in plasma lithium level, and to occur more often in women than in men. The efficacy of low-dose lithium prophylaxis and the significance of rebound relapse are discussed.