Prophylactic Trials Research Articles

Induction of Gag-specific T-cell responses by therapeutic immunization with a Gag-expressing Sendai virus vector in macaques chronically infected with simian-human immunodeficiency virus

Recent prophylactic vaccine trials inducing virus-specific CD8 + T-cell responses have shown control of primary infections of a pathogenic simian-human immunodeficiency virus (SHIV) in macaques. In the chronic phase, therapeutic immunization replenishing virus-specific CD8 + T-cells is likely to contribute to sustained control of virus replication. In this study, we have administered a recombinant Sendai virus (SeV) vector into five rhesus macaques that had received prophylactic vaccinations and had controlled SHIV replication for more than 1 year after challenge. Our results indicate that virus-specific CD8 + T-cell responses can be expanded and broadened by therapeutic immunization with SeV vectors in the chronic phase after prophylactic vaccine-based control of primary immunodeficiency virus infections.

Vaccination Against Cervical Cancer: Hopes and Realities.

Globally, carcinomas of the anogenital tract, in particular cervical cancer, remain some of the most common cancers in women, cervical cancer represents the second most frequent gynecological malignancy and the third leading cause of cancer-related death in women worldwide. The causal relationship between human papilomavirus (HPV) infection and anogenital cancer has prompted substantial interest in the development of both preventive and therapeutic vaccines against high-risk HPV types. In the past decade, several groups have shown encouraging results using experimental vaccination systems in animal models and these results have led to several current prophylactic and therapeutic vaccine clinical trials in humans. Prophylactic vaccination focuses on the induction of high titer neutralizing antibodies that are potentially protective against incident and persistent HPV infection. Two major phase II clinical trials conducted by pharmaceutical companies have demonstrated that their vaccines have 100% efficacy in preventing persistent viral DNA and its associated cellular abnormalities; however, whether they induce long-lasting protective immunity is yet to be determined. At least one US FDA approved prophylactic vaccine targeting the two most common high-risk HPVs is expected to be on the market within the next 2-3 years. Nevertheless, significant reductions in the frequency and onset of cytologic screening and incidences of HPV-related lesions are not expected to become apparent for decades due to the fact that there will be women who are already infected with HPV, the long latency period between infection and development of high-grade lesions, and lesions associated with other high-risk HPV types not being included in the vaccines. Therapeutic vaccines aim to control HPV-associated malignancies by stimulating cellular immune responses that target established HPV infections via viral proteins. Progress in the field of HPV immunotherapy has remained elusive, with clinical trials being limited to small numbers of patients. Potential treatment of precancerous lesions is unique to HPV-associated infection and cancer because of cytologic monitoring and HPV typing. Unlike more common surgical treatments for cervical lesions, active immunotherapy has the potential to address HPV persistence as the cause of lesion development in addition to leaving the patient with long-term immunity that can be reactivated if and when the patient becomes reinfected.

P.8.081 Prophylactic combination trials in bipolar disorder: the role of oxcarbazepine

This study aims to (a) describe what conflict (aggression, absconding etc.) and containment (de-escalation, restraining etc.) events occur before and after events of medication nonadherence on acute psychiatric wards and (b) identify which patient characteristics are associated with medication nonadherence.Conflict and containment events for each shift over the first 2 weeks of admission were coded retrospectively from nursing records for a sample of 522 adult psychiatric inpatients. The frequency and order of the conflict and containment events were identified. Univariate logistic regression models were conducted to examine which patient characteristics were linked with medication noncompliance.Medication refusals were commonly preceded by aggression whereas demands for pro re nata (PRN) (psychotropic) were commonly preceded by the same patient having been given PRN medication. Refusals and demands for medication were commonly followed by de-escalation and given PRN (psychotropic) medication. Only refusal of PRN medication was commonly followed by forced (intramuscular) medication. Ethnicity, previous self-harm and physical health problems were also linked to nonadherence.Greater attention to the conflict and containment events that precede and follow medication nonadherence may reduce the likelihood of medication nonadherence.

The Effect of Propranolol on Glyceryltrinitrate-Induced Headache and Arterial Response

Prophylactic drug trials in migraine are long-lasting and expensive and require long-term toxicology information. A human migraine model would therefore be helpful in testing new drugs. Immediate headache and delayed migraine after glyceryltrinitrate (GTN) has been well characterized. We have recently shown that sodium valproate has prophylactic effect in the GTN model. Here we report our experience with propranolol in this model. Nineteen subjects with migraine without aura and 16 sex- and aged-matched healthy subjects were included in a two-centre randomized double-blind cross-over study. Fourteen migraine subjects and 14 healthy subjects completed the study and results from comparison of the 28 subjects are reported. Randomly propranolol 160 mg or placebo were each given daily for 14 days to both migraine and healthy subjects. A 20-min intravenous infusion of GTN 0.25 microg/kg per min was administered on a study day at the end of both pretreatment periods. Headache was registered for 12 h after GTN infusions. Its intensity was scored on a numerical verbal rating scale from 0 to 10. Fulfilment of International Headache Society (HIS) criteria was recorded for 24 h. Radial and superficial temporal artery diameters and blood velocity of both middle cerebral arteries were measured. All migraine subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 5, range 0-7) compared with placebo (median 5, range 0-10) (P = 0.441). Eight of the 14 completing migraine subject developed IHS 1.1 migraine after GTN, two subjects on both days, three subjects only after placebo, and three subjects only after propranolol. No reduction of GTN-induced migraine was found after propranolol compared with placebo (5 vs. 5, P = 1.000). All healthy subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 2, range 1-5) compared with placebo (median 1, range 1-7) (P = 0.315). Two subjects fulfilled IHS criteria 1.1 for migraine without aura after propranolol but not after placebo. The fulfilment was short lasting and did not require rescue medication. Headache after GTN was more pronounced in migraine subjects than in healthy subjects both with (P = 0.003) and without pretreatment with propranolol (P = 0.017). We found that 2 weeks of propranolol constricted the radial artery in healthy subjects but not in migraine subjects. GTN-induced vasodilatation abolished this difference. Mean maximum blood flow velocity in the middle cerebral artery was higher in healthy subjects than in migraine patients (P = 0.003-0.033) and unaffected by propranolol. We observed no effect of propranolol on GTN-induced headache and migraine. This could indicate that GTN induces migraine at a deeper level of the pathophysiological cascade of migraine than the prophylactic effect of propranolol. Propranolol does not constrict cerebral arteries, which therefore cannot be part of its mechanism of action in migraine.

Antifungal Prophylaxis in Solid-Organ Transplant Recipients: Considerations for Clinical Trial Design

There are several key issues regarding clinical trial design for antifungal prophylaxis in organ transplant recipients. The existing and emerging data on the epidemiology and risk factors for invasive mycoses in organ transplant recipients formed the basis for discerning the subgroups that may be targeted for prophylaxis, the unique end points to be considered, and the attributes of currently available drugs that may be suitable candidates for antifungal prophylaxis. Epidemiological characteristics of invasive mycoses in organ transplant recipients have evolved sufficiently to warrant thoughtful reconsideration of the subsets of patients and the fungal pathogens to be targeted for antifungal prophylactic trials in the current era. Safety and tolerability of antifungal agents and outcome stratified by severity of illness are important end points given the potential for drug interactions with immunosuppressive agents and the fact that a beneficial effect of prophylaxis on outcome has been difficult to document in organ transplant recipients. Clinical trial design for antifungal prophylaxis must carefully consider the unique issues pertaining to the selection of patients most likely to benefit, as well as the tolerability and drug interactions of antifungal agents in organ transplant recipients.

How to Improve the Design of Trials of Antifungal Prophylaxis among Neutropenic Adults with Acute Leukemia

The risk for invasive fungal infections in patients with acute leukemia is generally low (4%-8%), and the routine use of fungal prophylaxis is not warranted except in specific high-risk groups that should be identified among this population. In a prophylactic study with a new agent, fluconazole or itraconazole oral solution represent good choices for the comparator because they are proven better than placebo or oral nonabsorbable antifungal agents in reducing the risk of invasive fungal infections in patients with acute leukemia. Because prophylaxis is most valuable when the risk of infection is high, patients with well-understood risk factors (severe mucosal disruption caused by chemotherapy, impaired cell-mediated immunity caused by steroids or fludarabine, use of a central venous catheter, and colonization by Candida species) should be selected. The end points for antifungal prophylactic trials should focus on proven and probable invasive fungal infections. Superficial and mucosal fungal infections do not represent a primary end point for these studies. Poor compliance should be considered as an interruption of treatment due to side effects and should be included in the criteria for failure. Fungus-related mortality should be evaluated as a failure of prophylaxis, whereas overall mortality may be influenced by many other cofactors. Differences in gastrointestinal toxicity of antifungal agents may limit the use of double-blind designs in some situations.

Vaccination to prevent and treat cervical cancer

Human papillomaviruses (HPVs) are the primary etiologic agents of cervical cancer. Thus, cervical cancer and other HPV-associated malignancies might be prevented or treated by HPV vaccines. Transmission of papillomavirus may be prevented by the generation of antibodies to capsid proteins L1 and L2 that neutralize viral infection. However, because the capsid proteins are not expressed at detectable levels by infected basal keratinocytes or in HPV-transformed cells, therapeutic vaccines generally target nonstructural early viral antigens. Two HPV oncogenic proteins, E6 and E7, are critical to the induction and maintenance of cellular transformation and are coexpressed in the majority of HPV-containing carcinomas. Thus, therapeutic vaccines targeting E6 and E7 may provide the best option for controlling HPV-associated malignancies. Various candidate therapeutic HPV vaccines are currently being tested whereby E6 and/or E7 are administered in live vectors, as peptides or protein, in nucleic acid form, as components of chimeric virus-like particles, or in cell-based vaccines. Encouraging results from experimental vaccination systems in animal models have led to several prophylactic and therapeutic vaccine clinical trials. If these preventive and therapeutic HPV vaccines prove successful in patients, as they have in animal models, then oncogenic HPV infection and its associated malignancies may be controllable by vaccination.

Ovarian neoplasms in patients with colorectal cancer: understanding the role of prophylactic oophorectomy.

Although the role of prophylactic oophorectomy is currently under debate and not well defined, it is of increasing and considerable relevance, especially in premenopausal women, particularly those with identifiable hereditary cancer syndromes. Patients with colorectal cancer with ovarian metastases are often symptomatic, require surgery, and have poor survival. Prophylactic oophorectomy abolishes the increased risk of primary ovarian cancer in these patients, resects synchronous metastases, and prevents development of metachronous ovarian metastases. Prophylactic oophorectomy trials, mostly conducted in postmenopausal women, have not shown survival advantage. In patients with ovarian metastases of colorectal cancer, maximal cytoreductive surgery followed by adjuvant therapy employing newer chemotherapeutic agents, whole abdominal irradiation with chemosensitization, or hyperthermic intraperitoneal chemotherapy may improve outcomes in selected patients.

Pentoxyfylline in and prevention and treatment of chronic lung disease.

The anti-inflammatory effects of pentoxfylline are associated with a number of clinical benefits. These include reduction in mortality in patients who have undergone bone marrow transplants or suffer peritonitis. In infants with sepsis, a reduction in mortality has also been associated with pentoxyfylline administration. The anti-inflammatory effects of pentoxyfylline, as well as its bronchodilator, diuretic and respiratory muscle stimulant effects suggest it may have a useful role in BPD. Interim analysis of a prophylactic trial suggests pentoxyfylline may reduce treatment requirements after the neonatal period and that, in established BPD, pentoxyfylline and dexamethasone may be of similar efficacy.

Placebo response in cluster headache trials: a review.

Probably because of its relative rarity as primary headache, there are few well-controlled clinical trials on cluster headache (CH) patients. Due to the severity of the pain, the placebo response in CH has been considered to be small. During the eighties the first double-blind, placebo-controlled trials were reported, and placebo responses demonstrated. Here we review the placebo response in CH trials in order to assess its magnitude and consider how future studies can be optimized. Six trials were identified with a double-blind, placebo-controlled, cross-over design testing treatments of acute CH. For those with a primary endpoint set to no or mild headache the placebo responses varied from 7 to 42%. In five of seven prophylactic trials, using a double-blind, placebo-controlled, parallel-group design, the placebo was merely used to set a baseline for comparison. The placebo responses were reported in only two trials. Here the response varies from 14 to 43%, the lowest value was reported using the strict endpoint; cessation of headache attacks. We conclude that a placebo response exists in trials of drugs on CH patients. Furthermore, this placebo response is of the same magnitude as that seen in migraine studies. We recommend the use of IHS guidelines when designing new trials. The possibility of a genuine biological mechanism responsible for the placebo response is discussed.

Development of HPV vaccines for HPV-associated head and neck squamous cell carcinoma.

High-risk genotypes of the human papillomavirus (HPV), particularly HPV type 16, are found in a distinct subset of head and neck squamous cell carcinomas (HNSCC). Thus, these HPV-associated HNSCC may be prevented or treated by vaccines designed to induce appropriate HPV virus-specific immune responses. Infection by HPV may be prevented by neutralizing antibodies specific for the viral capsid proteins. In clinical trials, vaccines comprised of HPV virus-like particles (VLPs) have shown great promise as prophylactic HPV vaccines. However, given that capsid proteins are not expressed at detectable levels by infected basal keratinocytes, vaccines with therapeutic potential must target other non-structural viral antigens. Two HPV oncogenic proteins, E6 and E7, are important in the induction and maintenance of cellular transformation and are co-expressed in the majority of HPV-containing carcinomas. Therefore, therapeutic vaccines targeting these proteins may have potential to control HPV-associated malignancies. Various candidate therapeutic HPV vaccines are currently being tested whereby E6 and/or E7 is administered in live vectors, in peptides or protein, in nucleic acid form, as components of chimeric VLPs, or in cell-based vaccines. Encouraging results from experimental vaccination systems in animal models have led to several prophylactic and therapeutic vaccine clinical trials. Should they fulfill their promise, these vaccines may prevent HPV infection or control its potentially life-threatening consequences in humans.

CURATIVE AND PROPHYLACTIC CONTROL OF FUNGAL LEAF ROT COMPLEX IN ROOT (WILT) AFFECTED COCONUT PALMS IN INDIA

Root wilt disease (RWD) is a debilitating malady of coconut in India that is caused by phytoplasma. In RWD affected palms, leaf rot disease (LRD) is commonly superimposed. The LRD is due to fungi and this leaf rot phase forms an integral part of RWD complex. Control of LRD is important as it severely disfigures the palm and brings about rapid deterioration in its health and productivity. Control trial involving Phytosanitation of young leaves, pouring of broad spectrum - systemic fungicide, Contaf 5 E (Hexaconazole 5% EC) into the axil of spindle leaf besides a number of other measures was conducted to study their ameliorating effect on LRD. Prophylactic control trial, especially with the broad-spectrum fungicides was also conducted. Pouring of Contaf into the axil of spindles along with phytosanitory measures on the spindle and other young leaves significantly reduced the incidence of LRD in newly emerging spindles effecting cure. Application of the fungicide on RWD palms prior to the onset of LRD, offered prophylactic protection to emerging leaves against LRD. Relevance of practising integrated control measures, cure of LRD at an early stage itself, the need for strict adoption of crop management technology etc. for effective disease control are highlighted here.

Failure to detect Chlamydia pneumoniae DNA in cerebral aneursymal sac tissue with two different polymerase chain reaction methods

Objective:Chlamydia pneumoniae (C pneumoniae) is a common cause of a usually mild, community acquired pneumonia. This organism, however, can spread from the respiratory tract into other parts of the body...

Eligibility and willingness of young Icelandic women to participate in a HPV vaccination trial

Cervical cancer is an important health problem worldwide, and the incidence of preinvasive cervical cancer is increasing among young sexually active women. The causal association between human papilloma virus (HPV) and cervical cancer makes it theoretically possible to eradicate the disease through vaccination. The aim of this study was to analyze the eligibility and willingness of 18-23-year-old Icelandic women to participate in a vaccination trial to prevent HPV infection and to assess knowledge of HPV. A questionnaire was formulated with questions on demographics, HPV knowledge, sexual behavior, attitude towards HPV vaccination, and other health-related issues. The questionnaire was tested on a subgroup of women before being mailed to 300 women aged 18-23 years, randomly selected by date of birth from the total population living in the Capital area of Reykjavík. The response rate of the mailed questionnaire was 54%. Of respondents, 96% reported having had sexual debut and 39% were aged 15 years or younger at first intercourse. Knowledge of HPV infections and associated diseases was limited, indicating the need for an educational campaign. Although 60% of the respondents were willing to participate in a HPV vaccination trial, the eligibility rate for the invited women was estimated to be approximately 13% (95% CI: 9-17%) after accounting for various exclusion criteria such as number of sexual partners, abnormal Pap smears, planning a pregnancy, or travelling abroad for more than 6 months. Icelandic women between 18 and 23 years of age have a sexual behavior profile and lifestyle that may decrease their eligibility in future prophylactic HPV vaccine trials. Improved education about HPV infection and its consequences is needed. Future trials may need to include younger women to improve recruitment.

T cell immunity to HIV: defining parameters of protection.

In recent years, CD4 and CD8 T cell responses to HIV and SIV infection have been increasingly measured with the use of single-cell assays such as ELISPOT, MHC-peptide oligomers, and cytokine flow cytometry. The results of these assays have been compared to those obtained with traditional bulk assays such as lymphoproliferation (by 3H-thymidine incorporation) and cytotoxicity (by 51Cr release). Such comparisons have led to some general understanding of the T cell responses that characterize progressive disease, long-term non-progressors, and individuals with viral suppression achieved by anti-retroviral therapy. In addition, prophylactic and therapeutic vaccine trials have also begun to use these assays of T cell immunity to gauge the immunogenicity of the vaccines. Whether such analyses will allow us to pick the best vaccine constructs, and whether they will provide us with an improved understanding of what constitutes protective cellular immunity to HIV, are major questions for the field. These questions will be examined in this review from the standpoint of current data and comparisons to other viral diseases. It is hypothesized that sophisticated multiparametric assays will be required to sort out the factors relevant for protective immunity in this complex disease. These parameters may include functional avidity, epitope breadth and specificity, proliferative capacity, cytokine repertoire, degree of anergy, and differentiation phenotype, as well as magnitude, of HIV-specific CD4 and CD8 T cells.

The design of prophylactic trials for HIV: the case of microbicides.

The design of prophylactic trials for HIV: the case of microbicides.

Commentary: The Design of Prophylactic Trials for HIV

Commentary: The Design of Prophylactic Trials for HIV

Sudden cardiac death in dilated cardiomyopathy -- therapeutic options.

Despite routine use of angiotensin-converting enzyme (ACE) inhibitors, beta-blockers and spironolactone in patients with heart failure due to dilated cardiomyopathy (DCM), these patients still have a considerable annual mortality rate of 5-10%. Sudden unexpected death accounts for up to 50% of all deaths and is most often due to rapid ventricular tachycardia or ventricular fibrillation and less often due to bradyarrhythmias or asystole. The use of beta-blockers in patients with heart failure has been shown to improve overall mortality considerably. This survival benefit has been demonstrated for bisoprolol, metoprolol and carvedilol. Therefore, one of these three beta-blocking agents should be administered routinely starting with low doses in all patients with New York Heart Association (NYHA) class II or III heart failure in addition to ACE inhibitors, unless there is a contraindication to beta-blocker use. In addition, NYHA class IV heart failure patients have been shown to benefit from carvedilol therapy, if tolerated. The conflicting results of GESICA and CHF-STAT studies do not support a strategy of "prophylactic" amiodarone therapy in patients with DCM in order to prevent sudden cardiac death. Despite growing evidence that implantable cardioverter defibrillator (ICD) therapy results in improved overall survival py preventing sudden cardiac death in patients at high risk for serious arrhythmic events, arrhythmia risk stratification with regard to prophylactic ICD implantation remains highly controversial in patients with DCM. This review describes potential arrhythmia mechanisms in DCM and summarizes the results of antiarrhythmic drug trials and of prophylactic ICD trials in patients with heart failure as well as our knowledge concerning arrhythmia risk stratification in patients with DCM.

Implementation of MADIT and MUSTT in clinical practice: results of an international survey.

The long-awaited dramatically positive outcome of the Multicenter Automatic Defibrillator Implantation Trial (MADIT II), just published by Moss et al.,(14) has generated cardiologists' interest on the implementation into clinical practice of that trial. Important lessons may be learned by examining the clinical implementation of two preceding randomized, prospective, prophylactic ICD trials: the original MADIT trial, published late 1996, and the Multicenter Unsustained Tachycardia Trial (MUSTT), published late 1999. Both demonstrated that implantable cardioverter defibrillators reduce all-cause mortality by over 50% in high risk patients without previous sustained arrhythmias. In early 2000, we surveyed 133 active electrophysiology centers (47 American, 81 European, 5 Canadian) to determine the extent to which these practices have been implemented in clinical practice during 1999, and the responses were compared to a similar survey for the year 1998. ICDs implanted for MADIT or MUSTT criteria accounted for 18% of new ICD implants in 1999, 65% greater than in 1998, increasing from 6% to 11% in Europe, and from 15% to 24% in America. During 1999, 53% of patients receiving ICDs for these indications were inpatients identified during hospitalization, 27% were outpatients referred specifically for MADIT/MUSTT indications, and 20% were identified by routine screening. Per the survey, in 1999 68% of responders were "somewhat (10-20%)" and 14% were "considerably (>20%)" more likely to implant ICDs for all indications. Extrapolating the results of this survey to all initial ICD implants for 1999, we estimate that 8500 implants for MADIT/MUSTT criteria took place in 1999, with the overall number of such implants substantially increased over the previous year, irrespective of geographic location, and influenced significantly by the publication of MUSTT. However, screening and implant practices between centers continue to vary over a broad spectrum. It will be interesting to observe whether similar patterns will follow with MADIT II.

Supraphysiological Doses of L-Thyroxine in the Maintenance Treatment of Prophylaxis-Resistant Affective Disorders

This prospective open-label study examined the efficacy of adjunctive supraphysiological doses of L-thyroxine (T4) in the maintenance treatment of prophylaxis-resistant affective disorder. Twenty-one (16 women, 5 men) of 25 patients enrolled consecutively over an 8-year period on the basis of their status of prophylaxis resistance (defined as two or more failures to standard prophylactic trials) participated for more than four months in the study and were eligible for the intention-to-treat analysis. The mean length of adjunctive treatment with T4 was 51.4 ± 21.7 months. The mean T4 dose at study end was 378.6 ± 90.2 μg/d. The number of episodes and hospitalizations, and the morbidity indices during the time of prophylactic T4 treatment, were compared with those measured for the same length of time before the start of T4 treatment (mirror-image method). On the Clinical Global Impression for Bipolar Disorder scale (CGI-BP, Change from Worst Phase of Illness), eleven subjects (52.4%) were rated as “very much improved”, four (19%) as “much improved”, two (9.5%) as “minimally improved” and four (19%) as “no change.” The mean total number of recurrences (8.6 before T4 treatment vs. 2.8 during T4 treatment; p = .004), the number of hospitalizations (3.1 vs. 1.9; p = .026) and the Morbidity Index (MITotal = 0.71 vs. MITotal = 0.28; p < .001) significantly declined during T4 treatment. Subjects with bipolar disorder (n = 13) benefited more from the T4 treatment intervention than did subjects with unipolar major depressive disorder (n = 4) and schizoaffective disorder (n = 4). In conclusion, adjunctive treatment with L-thyroxine in supraphysiological doses may be an effective strategy in the maintenance treatment of patients with prophylaxis-resistant affective disorders.