Exposition au VIH, à l'hépatite B et C au cabinet médical et à l'hôpital. Prévention et prophylaxie postexpositionnelle [Exposure to HIV, hepatitis B and C in office practice and hospital. Prevention and post-exposure prophylaxis]

Suite à un accident exposant à du sang (piqûre; coupure), provenant d'un patient infecté, le risque d'infection par VIH est d'environ 0,3% et par le virus de l'hépatite C (VHC) d'environ 0,5%. Chez les personnes vaccinées avec une réponse immunitaire adéquate (titre d'anticorps HBs >100 mUI/ml), aucune infection professionnelle par hépatite B n'a été reconnue en Suisse. La plupart des infections par VIH et VHB peuvent être prévenues par un traitement d'urgence et une prophylaxie postexpositionnelle (PEP). Il n'y a actuellement aucune prophylaxie postexpositionnelle pour le VHC. En cas de transmission de VHC, un traitement rapide par peginterféron et ribavirine est à envisager. Chaque hôpital et cabinet médical doivent mettre sur pied un système pour assurer une prise en charge optimale et en urgence des blessures par piqûres ou coupures. Lors de blessures accidentelles avec du sang de patients séropositifs pour le VIH et dans des situations complexes, il est recommandé de consulter un médecin du personnel ou un infectiologue expérimenté. The risk of infection after an occupational needle stick injury with blood from an infected source patient is approximately 0.3% for HIV and 0.5% for hepatitis C virus (HCV). In Switzerland no cases of occupational HBV infection have been recorded in fully vaccinated persons with a documented adequate vaccine response (HBsantibody titer >100 mIU/mL). Most occupational HIV und HBV infections can be prevented by appropriate emergency measures and post-exposure prophylaxis (PEP). No HCV-PEP is currently available. Early therapy with peginterferon and ribavirin should be considered in cases of occupational HCV seroconversion. Every hospital and office practice should establish a system for 24 h/24 h emergency management of occupational needle stick injuries. In the setting of an HIV-seropositive source patient and in complex situations, early consultation with a specialist in occupational medicine or infectious diseases should be considered.

Spare non-occupational HIV post-exposure prophylaxis by active contacting and testing of the source person.

OBJECTIVE: HIV-1 post-exposure prophylaxis (PEP) is frequently prescribed after exposure to source persons with an undetermined HIV serostatus. To reduce unnecessary use of PEP, we implemented a policy including active contacting of source persons and the availability of free, anonymous HIV testing ('PEP policy'). METHODS: All consultations for potential non-occupational HIV exposures i.e. outside the medical environment) were prospectively recorded. The impact of the PEP policy on PEP prescription and costs was analysed and modelled. RESULTS: Among 146 putative exposures, 47 involved a source person already known to be HIV positive and 23 had no indication for PEP. The remaining 76 exposures involved a source person of unknown HIV serostatus. Of 33 (43.4%) exposures for which the source person could be contacted and tested, PEP was avoided in 24 (72.7%), initiated and discontinued in seven (21.2%), and prescribed and completed in two (6.1%). In contrast, of 43 (56.6%) exposures for which the source person could not be tested, PEP was prescribed in 35 (81.4%), P < 0.001. Upon modelling, the PEP policy allowed a 31% reduction of cost for management of exposures to source persons of unknown HIV serostatus. The policy was cost-saving for HIV prevalence of up to 70% in the source population. The availability of all the source persons for testing would have reduced cost by 64%. CONCLUSION: In the management of non-occupational HIV exposures, active contacting and free, anonymous testing of source persons proved feasible. This policy resulted in a decrease in prescription of PEP, proved to be cost-saving, and presumably helped to avoid unnecessary toxicity and psychological stress.

Nonoccupational HIV post-exposure prophylaxis: a 10-year retrospective analysis.

BACKGROUND: We conducted a retrospective analysis of administration of nonoccupational HIV post-exposure prophylaxis (nPEP) in a single centre where tracing and testing of the source of exposure were carried out systematically over a 10-year period. METHODS: Files of all nPEP requests between 1998 and 2007 were reviewed. Characteristics of the exposed and source patients, the type of exposure, and clinical and serological outcomes were analysed. RESULTS: nPEP requests increased by 850% over 10 years. Among 910 events, 58% were heterosexual exposures, 15% homosexual exposures, 6% sexual assaults and 20% nonsexual exposures. In 208 events (23%), the source was reported to be HIV positive. In the remaining cases, active source tracing enabled 298 HIV tests to be performed (42%) and identified 11 HIV infections (3.7%). nPEP was able to be avoided or interrupted in 31% of 910 events when the source tested negative. Of 710 patients who started nPEP, 396 (56%) reported side effects, among whom 39 (5%) had to interrupt treatment. There were two HIV seroconversions, and neither was attributed to nPEP failure. CONCLUSIONS: nPEP requests increased over time. HIV testing of the source person avoided nPEP in 31% of events and was therefore paramount in the management of potential HIV exposures. Furthermore, it allowed active screening of populations potentially at risk for undiagnosed HIV infection, as shown by the increased HIV prevalence in these groups (3.7%) compared with a prevalence of 0.3% in Switzerland as a whole.

Immunologic work up of subjects who didn't respond appropriately to a rabies post exposure prophylaxis

Background New recommendations for rabies postexposure prophylaxis (rPEP) were published by the Centers for Disease Control and Prevention and the World Health Organization in 2010. In view of these new recommendations, the adequacy of rPEP among patients consulting the travel clinic of the University Hospital of Lausanne has been investigated and 6,8% of patients have been identified as non-responders with the new rPEP regimen. In this study we have selected the non-responders for a complete immunologic work up. Method Clinical and paraclinical immunologic investigations have been done to the non- responders patients. Those investigations have been conducted to look for an increased susceptibility to infections and an immunodeficiency. The investigations included a clinical evaluation, a full blood count, measurement of the immunoglobulin levels, a numeration of the subpopulations of the lymphocytes, a HIV test and an evaluation of the humoral response to tetanus, pneumococcal, and hepatitis B vaccinations. A lymphocyte proliferation assay with rabies antigen was performed to assess the cellular immune response. Results 9 subjects with rabies antibody titers ≤0,5 IU/ml after an rPEP with 4 doses were included in this study (=non-responders). 8/9 of these non-responders had an unremarkable medical history. 9/9 of them had normal paraclinical tests that did not suggest an immunodeficiency. The results of the lymphocyte proliferation assay with rabies antigen showed a significant correlation between the level of the humoral and cellular response. Conclusion These results suggest that a 4 dose intramuscular rPEP elicits in some patients a relatively poor humoral and cellular response, even in the absence of any immunosuppression. A serology on day 21 of the rPEP seems therefore useful to identify the patients who don't respond appropriately. Those non-responders should receive additional doses until they reach an antibody titer above 0.5 IU/ml.

The Reliability of Pre-travel History to Decide on Appropriate Counseling and Vaccinations: A Prospective Study.

BACKGROUND: Although medical and travel plans gathered from pre-travel interviews are used to decide the provision of specific pre-travel health advice and vaccinations, there has been no evaluation of the relevance of this strategy. In a prospective study, we assessed the agreement between pre-travel plans and post-travel history and the effect on advice regarding the administration of vaccines and recommendations for malaria prevention. METHODS: We included prospectively all consenting adults who had not planned an organized tour. Pre- and post-travel information included questions on destination, itineraries, departure and return dates, access to bottled water, plan of bicycle ride, stays in a rural zone, and close contact with animals. The outcomes measured included: agreement between pre- and post-travel itineraries and activities; and the effect of these differences on pre-travel health recommendations, had the traveler gone to the actual versus intended destinations for actual versus intended duration and activities. RESULTS: Three hundred and sixty-five travelers were included in the survey, where 188 (52%) were males (median age 38 years). In 81(23%) travelers, there was no difference between pre- and post-travel history. Disagreement between pre- and post-travel history were the highest for stays in rural zones or with local people (66% of travelers), close contact with animals (33%), and bicycle riding (21%). According to post-travel history, 125 (35%) travelers would have needed rabies vaccine and 9 (3%) typhoid fever vaccine. Potential overprovision of vaccine was found in <2% of travelers. A change in the malaria prescription would have been recommended in 18 (5%) travelers. CONCLUSIONS: Pre-travel history does not adequately reflect what travelers do. However, difference between recommendations for the actual versus intended travel plans was only clinically significant for the need for rabies vaccine. Particular attention during pre-travel health counseling should focus on the risk of rabies, the need to avoid close contact with animals and to seek care for post-exposure prophylaxis following an animal bite.

Repeated exposure to Lutzomyia intermedia sand fly saliva induces local expression of interferon-inducible genes both at the site of injection in mice and in human blood.

During a blood meal, Lutzomyia intermedia sand flies transmit Leishmania braziliensis, a parasite causing tegumentary leishmaniasis. In experimental leishmaniasis, pre-exposure to saliva of most blood-feeding sand flies results in parasite establishment in absence of any skin damages in mice challenged with dermotropic Leishmania species together with saliva. In contrast, pre-immunization with Lu. intermedia salivary gland sonicate (SGS) results in enhanced skin inflammatory exacerbation upon co-inoculation of Lu. intermedia SGS and L. braziliensis. These data highlight potential unique features of both L. braziliensis and Lu. intermedia. In this study, we investigated the genes modulated by Lu. intermedia SGS immunization to understand their potential impact on the subsequent cutaneous immune response following inoculation of both SGS and L. braziliensis. The cellular recruitment and global gene expression profile was analyzed in mice repeatedly inoculated or not with Lu. intermedia. Microarray gene analysis revealed the upregulation of a distinct set of IFN-inducible genes, an immune signature not seen to the same extent in control animals. Of note this INF-inducible gene set was not induced in SGS pre-immunized mice subsequently co-inoculated with SGS and L. braziliensis. These data suggest the parasite prevented the upregulation of this Lu. intermedia saliva-related immune signature. The presence of these IFN-inducible genes was further analyzed in peripheral blood mononuclear cells (PBMCs) sampled from uninfected human individuals living in a L. braziliensis-endemic region of Brazil thus regularly exposed to Lu. intermedia bites. PBMCs were cultured in presence or absence of Lu. intermedia SGS. Using qRT-PCR we established that the IFN-inducible genes induced in the skin of SGS pre-immunized mice, were also upregulated by SGS in PBMCs from human individuals regularly exposed to Lu. intermedia bites, but not in PBMCs of control subjects. These data demonstrate that repeated exposure to Lu. intermedia SGS induces the expression of potentially host-protective IFN-inducible genes.

Appropriate management of special situations in Crohn's disease (upper gastro-intestinal; extra-intestinal manifestations; drug safety during pregnancy and breastfeeding): results of a multidisciplinary international expert panel-EPACT II

Introduction: High-grade evidence is lacking for most therapeutic decisions in Crohn's disease. Appropriateness criteria were developed for upper gastro-intestinal, extra-intestinal manifestations and drug safety during conception, pregnancy and breastfeeding in patients with Crohn's disease, to assist the physician in clinical decision making. Methods: The European Panel on the Appropriateness of Crohn's Disease Therapy (EPACT II), a multidisciplinary international European expert panel, rated clinical scenarios based on evidence from the published literature and panelists' own clinical expertise. Median ratings (on a 9-point scale) were stratified into three categories: appropriate (7-9), uncertain (4-6 with or without disagreement) and inappropriate (1-3). Experts were also asked to rank appropriate medications by priority. Results: Proton pump inhibitors, steroids, azathioprine/6-mercaptopurine and infliximab are appropriate for upper gastro-duodenal Crohn's disease; for stenosis, endoscopic balloon dilation is the first-tine therapy, although surgery is also appropriate. Ursodeoxycholic acid is the only appropriate treatment for primary sclerosing cholangitis. Infliximab is appropriate for Pyoderma gangrenosum, ankylosing spondylitis and uveitis, steroids for Pyoderma gangrenosum and ankylosing spondylitis, adalimumab for Pyoderma gangrenosum and ankylosing spondylitis, cyclosporine-A/tacrolimus for Pyoderma gangrenosum. Mesalamine, sulfasalazine, prednisone, azathioprine/6-mercaptopurine, ciprofloxacin, and probiotics, may be administered safety during pregnancy or for patients wishing to conceive, with the exception that mate patients considering conception should avoid sulfasalazine. Metronidazol is considered safe in the 2nd and 3rd trimesters whereas infliximab is rated safe in the 1st trimester but uncertain in the 2nd and 3rd trimesters. Methotrexate is always contraindicated at conception, during pregnancy or during breastfeeding, due to its known teratogenicity. Mesalamine, prednisone, probiotics and infliximab are considered safe during breastfeeding. Conclusion: EPACT II recommendations are freely available online (www.epact.ch). The validity of these criteria should now be tested by prospective evaluation. (C) 2009 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Disposition of oral valganciclovir during continuous renal replacement therapy in two lung transplant recipients

Background: Oral valganciclovir (VGC) is hydrolysed into active ganciclovir (GCV) which is eliminated in the kidney by filtration and secretion. VGC dosage has to be adapted in renal failure with continuous renal replacement therapy (CRRT), a condition sometimes encountered early after solid organ transplantation. This investigation aimed to determine whether VGC 450 mg every 48 hours provides appropriate GCV exposure for cytomegalovirus (CMV) prophylaxis during CRRT. Methods: GCV pharmacokinetics were extensively studied during CRRT in two lung transplant recipients with acute renal failure receiving VGC 450 mg every 48 hours trough a nasogastric tube. In vitro experiments using blank whole blood spiked with GCV further investigated exchanges between plasma and erythrocytes. Results: GCV disposition was characterised by an area under the curve (AUC) of 98.0 and 55.4 mg h/L, resulting in trough concentrations of 0.7 and 0.2 mg/L, an apparent total body clearance of 3.3 and 5.8 L/h, a terminal half-life of 16.9 and 14.1 h, and an apparent volume of distribution of 60.3 and 104.9 L. The observed sieving coefficient (filtrate/plasma) was 1.05 and 0.96, and the hemofiltration clearance 3.3 and 3.1 L/h, respectively. High sieving values could be explained by an efflux of GCV from erythrocytes. In vitro experiments confirmed that erythrocytes are loaded with significant GCV amount and release it quickly into plasma, thus contributing to the apparent efficacy of hemofiltration. Conclusion: These results indicate that a VGC dosage of 450 mg every 48 hours was adequate for CMV prophylaxis during CRRT, providing GCV levels similar to those reported using 900 mg qd in transplant recipients with normal renal function.

Médicaments et allaitement: quelques éléments à considérer avant de les juger incompatibles [Drugs and breastfeeding: some facts to consider before deciding they are incompatible]

Breastfeeding is considered the ideal way of providing young infants with the required nutrients for healthy growth and development. An increase in the prevalence and duration of breastfeeding has been observed over the last years in response to promotion campaigns. When a medicamentous treatment is started, discontinuation of breastfeeding is often proposed, for fear of harmful consequences for the infant. Nevertheless such a decision is not unimportant, and it appears that many drugs can actually be used during breastfeeding without significant risk. An assessment of the real risk incurred by exposed children makes it possible to avoid unnecessary discontinuations of breastfeeding. This article aims to review the facts needed to assess amount of drug exposure to the child and to list the few drugs associated with significant effects on the nursing infant.

Underreporting of needlestick and sharps injuries among healthcare workers in a Swiss University Hospital.

OBJECTIVES: To determine 1) rates of needlestick and sharps injuries (NSSIs) not reported to occupational health services, 2) reasons for underreporting and 3) awareness of reporting procedures in a Swiss university hospital. MATERIALS AND METHODS: We surveyed 6,367 employees having close clinical contact with patients or patient specimens. The questionnaire covered age, sex, occupation, years spent in occupation, history of NSSI during the preceding twelve months, NSSI reporting, barriers to reporting and knowledge of reporting procedures. RESULTS: 2,778 questionnaires were returned (43.6%) of which 2,691 were suitable for analysis. 260/2,691 employees (9.7%) had sustained at least one NSSI during the preceding twelve months. NSSIs were more frequent among nurses (49.2%) and doctors performing invasive procedures (IPs) (36.9%). NSSI rate by occupation was 8.6% for nurses, 19% for doctors and 1.3% for domestic staff. Of the injured respondents, 73.1% reported all events, 12.3% some and 14.6% none. 42.7% of doctors performing invasive procedures (IPs) underreported NSSIs and represented 58.6% of underreported events. Estimation that transmission risk was low (87.1%) and perceived lack of time (34.3%) were the most common reasons for non-reporting. Regarding reporting procedures, 80.1% of respondents knew to contact occupational health services. CONCLUSION: Doctors performing IPs have high rates of NSSI and, through self-assessment that infection transmission risk is low or perceived lack of time, high rates of underreporting. If individual risk analyses underestimate the real risk, such underreporting represents a missed opportunity for post-exposure prophylaxis and identification of hazardous procedures. Doctors' training in NSSI reporting merits re-evaluation.

Health effects of occupational exposure to traffic particles and noise

Exposure to fine particles and noise has been linked to cardiovascular diseases and elevated cardiovascular mortality affecting the worldwide population. Residence and/or work in proximity to emission sources as for example road traffic leads to an elevated exposure and a higher risk for adverse health effects. Highway maintenance workers spend most of their work time in traffic and are exposed regularly to particles and noise. The aims of this thesis were to provide a better understanding of the workers' mixed exposure to particles and noise and to assess cardiopulmonary short term health effects in relation to this exposure. Exposure and health data were collected in collaboration with 8 maintenance centers of the Swiss Road Maintenance Services located in the cantons Bern, Fribourg and Vaud in western Switzerland. Repeated measurements with 18 subjects were conducted during 50 non-consecutive work shifts between Mai 2010 and February 2012, equally distributed over all seasons. In the first part of this thesis we tested and validated measurements of ultrafine particles with a miniature diffusion size classifier (miniDiSC) - a novel particle counting device that was used for the exposure assessment during highway maintenance work. We found that particle numbers and average particle size measured by the miniDiSC were highly correlated with data from the P-TRAK, a condensation particle counter (CPC), as well as from a scanning mobility particle sizer (SMPS). However, the miniDiSC measured significantly more particles than the P-TRAK and significantly less than the SMPS in its full size range. Our data suggests that the instrument specific cutoffs were the main reason for the different particle counts. The first main objective of this thesis was to investigate the exposure of highway maintenance workers to air pollutants and noise, in relation to the different maintenance activities. We have seen that the workers are regularly exposed to high particle and noise levels. This was a consequence of close proximity to highway traffic and the use of motorized working equipment such as brush cutters, chain saws, generators and pneumatic hammers during which the highest exposure levels occurred. Although exposure to air pollutants were not critical if compared to occupational exposure limits, the elevated exposure to particles and noise may lead to a higher risk for cardiovascular diseases in this worker population. The second main objective was to investigate cardiopulmonary short-term health effects in relation to the particle and noise exposure during highway maintenance work. We observed a PM2.5 related increase of the acute-phase inflammation markers C-reactive protein and serum amyloid A and a decrease of TNFa. Heart rate variability increased as a consequence of particle as well as noise exposure. Increased high frequency power indicated a stronger parasympathetic influence on the heart. Elevated noise levels during recreational time, after work, were related to increased blood pressure. Our data confirmed that highway maintenance workers are exposed to elevated levels of particles and noise as compared to the average population. This exposure poses a cardiovascular health risk and it is therefore important to make efforts to better protect the workers health. The use of cleaner machines during maintenance work would be a major step to improve the workers' situation. Furthermore, regulatory policies with the aim of reducing combustion and non-combustion emissions from road traffic are important for the protection of workers in traffic environments and the entire population.

Reproducibility of acute mountain sickness in children and adults: a prospective study.

OBJECTIVE: Although a history of previous acute mountain sickness (AMS) is commonly used for providing advice and recommending its prophylaxis during subsequent exposure, the intraindividual reproducibility of AMS during repeated high-altitude exposure has never been examined in a prospective controlled study.METHODS: In 27 nonacclimatized children and 29 adults, AMS was assessed during the first 48 hours after rapid ascent to 3450 m on 2 consecutive occasions 9 to 12 months apart.RESULTS: During the first exposure, 18 adults (62%) and 6 children (22%) suffered from AMS; during the second exposure, 14 adults (48%) and 4 children (15%) suffered from this problem (adults versus children, P <= .01). Most importantly, the intraindividual reproducibility of AMS was very different (P < .001) between children and adults. None of the 6 children having suffered from AMS during the first exposure suffered from AMS during the second exposure, but 4 children with no AMS during the first exposure did experience this problem during the second exposure. In contrast, 14 of the 18 adults who suffered from AMS on the first occasion also presented with this problem during the second exposure, and no new case developed in those who had not experienced AMS on the first occasion.CONCLUSIONS: In adults, a history of AMS is highly predictable of the disease on subsequent exposure, whereas in children it has no predictive value. A history of AMS should not prompt practitioners to advise against reexposure to high altitude or to prescribe drugs for its prophylaxis in children. Pediatrics 2011;127:e1445-e1448

Vaccinia immune globulin: current policies, preparedness, and product safety and efficacy.

In 1980 the World Health Organization declared that smallpox was eradicated from the world, and routine smallpox vaccination was discontinued. Nevertheless, samples of the smallpox virus (variola virus) were retained for research purposes, not least because of fears that terrorist groups or rogue states might also have kept samples in order to develop a bioweapon. Variola virus represents an effective bioweapon because it is associated with high morbidity and mortality and is highly contagious. Since September 11, 2001, countries around the world have begun to develop policies and preparedness programs to deal with a bioterror attack, including stockpiling of smallpox vaccine. Smallpox vaccine itself may be associated with a number of serious adverse events, which can often be managed with vaccinia immune globulin (VIG). VIG may also be needed as prophylaxis in patients for whom pre-exposure smallpox vaccine is contraindicated (such as those with eczema or pregnant women), although it is currently not licensed in these cases. Two intravenous formulations of VIG (VIGIV Cangene and VIGIV Dynport) have been licensed by the FDA for the management of patients with progressive vaccinia, eczema vaccinatum, severe generalized vaccinia, and extensive body surface involvement or periocular implantation following inadvertent inoculation.

Acute respiratory syndrome after inhalation of waterproofing sprays: a posteriori exposure-response assessment in 102 cases

Waterproofing agents are widely used to protect leather and textiles in both domestic and occupational activities. An outbreak of acute respiratory syndrome following exposure to waterproofing sprays occurred during the winter 2002-2003 in Switzerland. About 180 cases were reported by the Swiss Toxicological Information Centre between October 2002 and March 2003, whereas fewer than 10 cases per year had been recorded previously. The reported cases involved three brands of sprays containing a common waterproofing mixture, that had undergone a formulation change in the months preceding the outbreak. A retrospective analysis was undertaken in collaboration with the Swiss Toxicological Information Centre and the Swiss Registries for Interstitial and Orphan Lung Diseases to clarify the circumstances and possible causes of the observed health effects. Individual exposure data were generated with questionnaires and experimental emission measurements. The collected data was used to conduct numeric simulation for 102 cases of exposure. A classical two-zone model was used to assess the aerosol dispersion in the near- and far-field during spraying. The resulting assessed dose and exposure levels obtained were spread on large scales, of several orders of magnitude. No dose-response relationship was found between exposure indicators and health effects indicators (perceived severity and clinical indicators). Weak relationships were found between unspecific inflammatory response indicators (leukocytes, C-reactive protein) and the maximal exposure concentration. The results obtained disclose a high interindividual response variability and suggest that some indirect mechanism(s) predominates in the respiratory disease occurrence. Furthermore, no threshold could be found to define a safe level of exposure. These findings suggest that the improvement of environmental exposure conditions during spraying alone does not constitute a sufficient measure to prevent future outbreaks of waterproofing spray toxicity. More efficient preventive measures are needed prior to the marketing and distribution of new waterproofing agents.

Six years of denosumab treatment in postmenopausal women with osteoporosis: results from the first three years of the freedom extension

Background/Purpose: Denosumab (DMAb) is an approved therapy for the treatment of postmenopausal women with osteoporosis at increased risk for fracture. A favorable risk/benefit profile was demonstrated in the pivotal, 3-year FREEDOM trial (Cummings et al NEJM 2009). The open-label, active-treatment FREEDOM Extension study is investigating the efficacy and safety of DMAb for up to 10 years. The Extension trial enrolled women who had received DMAb or placebo in FREEDOM and provides an opportunity to evaluate the long-term efficacy and safety of continuous DMAb treatment (long-term group), and to replicate the DMAb findings observed in FREEDOM (cross-over group). Here, we report the results from the first 3 years of the Extension, representing up to 6 continuous years of DMAb exposure.Methods: During the Extension, each woman is scheduled to receive 60 mg DMAb every 6 months and supplemental calcium and vitamin D daily. For the analyses reported here, women from the FREEDOM DMAb group received 3 more years of DMAb for a total of 6 years of exposure (long-term group) and women from the FREEDOM placebo group received 3 years of DMAb exposure (cross-over group).Results: Of the 5928 women eligible for the Extension, 4550 (77%) enrolled (N_2343 long-term; N_2207 cross-over). In the long-term group, further significant mean increases in bone mineral density (BMD) occurred 4044 for cumulative 6-year gains of 15.2% at the lumbar spine and 7.5% at the total hip (Figure). During the first 3 years of DMAb treatment during the Extension, the cross-over group had significant mean gains in BMD at the lumbar spine (9.4%) and total hip (4.8%), similar to those observed in the long-term DMAb group during the first 3 years of FREEDOM (lumbar spine, 10.1%; total hip, 5.7%). Serum CTX was rapidly and similarly reduced after the 1st (cross-over) or 7th (long-term) DMAb dose with the characteristic attenuation observed at the end of the dosing period. In the cross-over group, yearly incidences of new vertebral and nonvertebral fractures were lower than in the FREEDOM placebo group. Fracture incidence remained low in the long-term group. Incidences of adverse events (AEs) and serious AEs did not increase over time with DMAb treatment. There were 2 subjects with AEs adjudicated to ONJ in the cross-over group and 2 in the long-term group. Both cases in the cross-over group healed completely and without further complications; 1 of these subjects continues to receive DMAb. Both women in the long-term group continue to be followed. No atypical femur fractures have been observed to date. Figure. Percent changes in bone mineral density during FREEDOM and the Extension Conclusion: DMAb treatment for 6 continuous years (long-term group) remained well tolerated, maintained reduced bone turnover, and continued to significantly increase BMD. Fracture incidence remained low. DMAb treatment for 3 years in the cross-over group reproduced the original observations in FREEDOM.