Views of European Drug Development Stakeholders on Treatment Optimization and Its Potential for Use in Decision-Making.

BACKGROUND: The current drug development paradigm has been criticized for being too drug-centered and for not adequately focusing on the patients who will eventually be administered the therapeutic interventions it generates. The drug-driven nature of the present framework has led to the emergence of a research gap between the pre-approval development of anticancer medicines and their post-registration use in real-life clinical practice. This gap could potentially be bridged by transitioning toward a patient-centered paradigm that places a strong emphasis on treatment optimization, which strives to optimize the way health technologies are applied in a real-world environment. However, questions remain concerning the ideal features of treatment optimization studies and their acceptability among key stakeholders. OBJECTIVES: The aim of this study was to explore the views of key stakeholders in the drug development process regarding the concept of treatment optimization. METHODS: Semi-structured interviews were conducted between December 2018 and May 2019 with 26 participants across ten EU Member States and six different stakeholder groups, including academic clinicians as well as representatives of patient organizations, regulatory authorities, health technology assessment agencies, payers, and industry. RESULTS: Based on the input of the experts interviewed, clarification was obtained regarding the optimal features of treatment optimization studies in terms of their conduct, funding, timing, design, and setting. Moreover, a number of opportunities and challenges of undertaking such trials were identified. Inter-stakeholder discussion during their design was seen as desirable. There was also broad support among the participants for regulatory measures to facilitate treatment optimization, although there was no agreement on the optimal scale and nature of these initiatives. Furthermore, the interviewees believed that the evidence strength of well-designed treatment optimization studies performed according to rigorous quality standards is greater than or at least equal to that of classical clinical trials. In addition, there was a strong consensus that the results of treatment optimization studies should be taken into account during the decision-making of regulators, payers, and/or clinicians. CONCLUSIONS: Stakeholders involved in drug development consider treatment optimization studies to be valuable tools to address current evidence gaps and support their implementation into the existing research framework.

Breast Tuberculosis in Women: A Systematic Review.

Breast tuberculosis (TB) is rarely reported and poorly described. This review aims to update the existing literature on risk factors, clinical presentations, constitutional symptoms, diagnostic procedures, and medical and surgical treatments for breast TB. In all, 1,478 cases of breast TB were collected. Previous history of TB was reported in 19% of cases. The most common clinical appearance of the lesion was breast lump (75%). The most common associated finding was axillary lymphadenitis (33%) followed by sinus or fistula (24%). The most common symptoms were pain and fever, reported in 42% and 28% of cases, respectively. The most used diagnostic method was fine-needle aspiration cytology (32%), followed by biopsy (27%), acid-fast bacteria Ziehl-Neelsen stain (26%), culture (13%), and polymerase chain reaction (2%). These tested positive in 64%, 93%, 27%, 26%, and 58% of cases, respectively. The majority (69%) of patients received a 6-month anti-TB treatment (isoniazid, rifampicin, pyrazinamide, and ethambutol). Surgery consisted of excision in 39% of cases, drainage in 23%, and mastectomy in 5%. The great majority of patients had a positive outcome. It often mimics breast cancer, which makes it difficult to diagnose. Most patients, when diagnosed in time, respond to antitubercular therapy alone.

Breast tuberculosis in men: A systematic review.

SETTING: Breast tuberculosis in male is a rarely reported and poorly described condition. OBJECTIVE: To quantify the number of breast tuberculosis in men, to describe clinical presentation and to present the diagnostic and therapeutic procedures applied. DESIGN: A systematic review of the literature including reports published in English, Spanish and French until December 2017. RESULTS: The search yielded 26 cases of male breast tuberculosis, median age 56.5 years. Most presented with an isolated breast lump (89%), associated with axillary lymphadenitis (27.8%) and skin inflammation (33.3%). The most common constitutional symptoms were pain (64.7%) and fever (35.3%). Fine-needle aspiration cytology and culture were the most common diagnostic modality (61.5%). Standard anti-tuberculosis regimen was the main treatment, alone or accompanied or preceded by incision and drainage. CONCLUSIONS: The risk of breast tuberculosis in men appears to be low, but the condition can be difficult to diagnose and the diagnostic delays can be long. Overall prognosis is good following standard anti-tuberculosis regimen with or without incision/drainage.

Tobacco addiction and smoking status in heroin addicts under methadone vs. buprenorphine therapy.

Aims of the present investigation were: (i) to assess the prevalence of current smokers and relative smoking status among a large number of heroin addicts attending opioid-substitution therapy prevalence; (ii) to evaluate the relationship between the type (methadone, buprenorphine) and dosage of opioid substitution therapy and nicotine dependence. Three hundred and five (305) heroin addicts under opioid-substitution therapy were recruited at five Addiction Units. All participants completed a questionnaire assessing sociodemographic information, type and dose of opioid-substitution therapy, smoking history and status, Fagerström Test for Nicotine Dependence (FTND), and the Zung Self-Rating Depression scale (SDS). 298 subjects, out of 305 (97.2%) were smokers, with an average of 20.5 cigarette/day and a median FTND of 6. Our data confirmed the high prevalence of smokers among heroin addicts, the highest described in the literature to date among heroin addicts under substitution therapies, without any significant difference between methadone vs. buprenorphine therapy groups. There was no correlation between dose of methadone or buprenorphine and average number of cigarettes/day. Patients in substance abuse treatment very frequently smoke cigarettes and often die of tobacco-related diseases. Substance abuse treatment programs too often ignore tobacco use. We hope that these findings will help to incorporate smoking cessation in substance abuse treatments.

Seroprevalence of HIV, HSV-2, and Treponema pallidum in the Kosovarian population.

The objective of this study was to evaluate the seroprevalence of infection with HIV, herpes simplex virus type 2 (HSV-2), and Treponema pallidum (TP) in a Kosovarian population. A cross-sectional study was performed in Peja, Kosovo, from January to March 2005, among 1285 persons recruited at the Peja Hospital. The seroprevalence of HIV, HSV-2, and TP was evaluated, and the viral correlates for each infection were analysed. No HIV-positive cases were found. The seroprevalence of HSV-2 was 20.2%. The factors significantly associated with HSV-2 infection at the multivariate analysis were: female gender (adjusted OR, 1.73; 95% CI 1.24-2.41) and being married (adjusted OR, 1.46; 95% CI 1.06-2.01). Three persons (0.2%) had a positive serology for TP. The only risk factor associated with TP infection was age = 50 y. Our results show a low seroprevalence of HIV infection and TP, and a high seroprevalence of HSV-2 in Kosovo. These findings suggest the need for appropriate surveillance systems, prevention programmes, and information aimed at controlling the spread of HIV and other sexually transmitted infections in this area. Moreover, the circulation of infections acquired through sexual contact may facilitate an increase in the sexually transmitted HIV epidemic in the near future.

Erectile dysfunction in male heroin users, receiving methadone and buprenorphine maintenance treatment.

Erectile dysfunction (ED) is common among people in treatment for heroin addiction. The purpose of the study was to examine the frequency of ED among methadone and buprenorphine maintenance therapy patients, and to identify factors associated with ED. Patients - recruited from 7 centres in Italy - underwent: (i) a structured interview on socio-demographic characteristics, drug use and sexual behaviour; (ii) IIEF-15 test, a test of sexual function; (iii) Zung test for depression. The study included 201 males: 42% were on methadone maintenance, 58% were on buprenorphine. Overall, 58% reported no ED, 24% reported mild to moderate ED, and 18% severe ED. In univariate analysis buprenorphine patients had less ED than methadone patients (p=0.0135). Subjects living with a partner had less ED than others (p=0.0018). More depressed subjects had more ED (p<0.001). Heterosexual patients reported less ED than homo/bisexual patients (p=0.0427), and partner's use of heroin was associated with more ED (p=0.0078). The significant univariate predictors were entered into a cumulative logit model. Living with a sexual partner was associated with a lower likelihood of ED, while depression, having a sexual partner with a history of drug use and not having a steady partner were associated with a greater likelihood of ED. The significant association between treatment and ED which appeared in univariate analysis (with buprenorphine patients reporting less ED than methadone patients) was not confirmed by the multivariate analysis. Both psychological and social factors were associated with ED which is an important problem for many males in methadone and buprenorphine treatment.

Patients in long-term maintenance therapy for drug use in Italy: analysis of some parameters of social integration and serological status for infectious diseases in a cohort of 1091 patients.

BACKGROUND: Heroin addiction often severely disrupts normal social functioning. The aims of this multi-centre study of heroin users in long-term replacement treatment were: i) to provide information on aspects of social condition such as employment, educational background, living status, partner status and any history of drug addiction for partners, comparing these data with that of the general population; ii) to assess the prevalence of hepatitis, syphilis and HIV, because serological status could be a reflection of the social conditions of patients undergoing replacement treatment for drug addiction; iii) to analyse possible relationships between social conditions and serological status. METHODS: A cross-sectional study was carried out in sixteen National Health Service Drug Addiction Units in northern Italy. The data were collected from February 1, 2002 to August 31, 2002. Recruitment eligibility was: maintenance treatment with methadone or buprenorphine, treatment for the previous six months, and at least 18 years of age. In the centres involved in the study no specific criteria or regulations were established concerning the duration of replacement therapy. Participants underwent a face-to-face interview. RESULTS: The conditions of 1091 drug treatment patients were evaluated. The mean duration of drug use was 14.5 years. Duration was shorter in females, in subjects with a higher educational background, and in stable relationships. Most (68%) had completed middle school (11-14 years of age). Seventy-nine percent were employed and 16% were unemployed. Fifty percent lived with their parents, 34% with a partner and 14% alone. Males lived more frequently with their parents (55%), and females more frequently with a partner (60%). Sixty-seven percent of male patients with a stable relationship had a partner who had never used heroin. HCV prevalence was 72%, HBV antibodies were detected in 42% of patients, while 30% had been vaccinated; 12.5% of subjects were HIV positive and 1.5% were positive for TPHA. CONCLUSION: A significant percentage of heroin users in treatment for opiate addiction in the cohort study have characteristics which indicate reasonable integration within broader society. We posit that the combination of effective treatment and a setting of economic prosperity may enhance the social integration of patients with a history of heroin use.

Prevalence of hepatitis A among drug users in north-eastern Italy. Is vaccination necessary in low prevalence areas?

BACKGROUND: The authors report on the prevalence of, and risk factors for, hepatitis A virus (HAV) in a group of drug users in Italy. METHODS: 404 heroin users were recruited and compared with a control group of 107 subjects in the general population. RESULTS: Drug users born in north-eastern Italy have a prevalence of anti-HAV similar to the control group. A much higher prevalence was found in drug users born in southern Italy. CONCLUSION: The similar prevalence of anti-HAV in drug users born in north-eastern Italy and in the general population, suggests that their lifestyle does not involve a substantial additional risk of HAV. The much higher prevalence found in drug users born in southern Italy is more likely to be related to infection during infancy.

Heterosexual relationships among heroin users in Italy.

This study investigated how many stable partners of drug users (DUs) had a history of drug use or were current DUs. Of 589 DUs interviewed, 41% reported that they had a partner with current or previous experience of drug addiction. A strong gender difference emerged: 77% of female DUs reported a stable relationship with partners with a history of addiction, versus only 30% for male DUs. Partners with a history of drug dependence are more likely to be: male, older, with a lower educational level and a lower rate of stable employment than partners without a history of drug addiction. Logistic regression analysis indicated that the characteristics of heroin users who have current partners with histories of drug use include: female gender, older age, living with a partner, lengthy duration of the relationship and HIV positive status. Fewer subjects are married if the partner has a history of addiction, and there is an association between lengthy drug use and partner without drug addiction history. The high percentage (59%) of subjects who were in stable relationships with partners without histories of heroin addiction and the relatively long duration of these relationships, raises the issue of possible transmission of blood-borne viruses from the DUs to their sexual partners. The study does suggest the need for consideration of sexual partnerships and gender differences in providing drug abuse treatment for heroin users.

Progressive decrease of hepatitis B in a cohort of drug users followed over a period of 15 years: the impact of anti-HBV vaccination.

In the Western world, the population at the highest risk of HBV infection is probably that of illicit drug users (DUs). Since 1985, 1 Public Health Centre for Drug Users (PHCDU), in north-eastern Italy, has been asking all heroin DUs, whether in treatment or not, to undergo screening for HIV, HBV and, since 1989, for HCV infection. Since 1988 the Centre has proposed HBV vaccination to all patients who were negative for all HBV markers. From 1985 to 2001 895 heroin DUs were screened, 726 males and 169 females. 442 (49.4%) were negative to HBV markers at the first control and 72.4% received at least 1 dose of the vaccine. 320 DUs were vaccinated and a total of 995 doses of recombinant vaccine were administered. The anti-HBc antibody appeared in 2 vaccinated patients out of 258 DUs undergoing controls, while 13 seroconversions for anti-HBc occurred in 45 DUs who had refused to be vaccinated. On the basis of these results, HBV vaccination of DUs can be strongly recommended. Vaccination showed a good adherence in a population difficult to treat and can have a leading role in reducing HBV infection in DUs and their contacts.

[Curing smoking: a priority health objective]. / Curare il tabagismo: un obiettivo di salute prioritario.

Cigarette smoking is the number one avoidable killer in the industrial world. Yet doctors frequently do not treat or prevent the disease as they should. Education and training are lacking. In the present article an overview of these and other smoking-related problems and, at the same time, a description of the practical management of an outpatient clinic for smoking cessation, the epidemiology of smoking, the related risks and mortality, as well as the advantages of quitting are presented. The toxicology and pharmacology are discussed, in relation to addiction and craving. The article also includes the diagnosis of nicotine-dependence and nicotine replacement as well as bupropione and acupuncture treatments. The gain in body weight, depression and relapse are also dealt with. The various and personally tailored therapeutic strategies used in a service operating in a setting of Internal Medicine are presented and discussed.

Prevalence of tuberculosis infection and comparison of multiple-puncture liquid tuberculin test and Mantoux test among drug users.

In order to determine the prevalence of latent infection due to Mycobacterium tuberculosis in drug users and to provide centres for drug users with a practical tool for tuberculosis screening, 237 drug users were subjected to the Monotest and, for reference purposes, to the Mantoux test. The overall prevalence of subjects with a tuberculin skin reaction size > or = 5 mm in the Mantoux test was 25.7%; utilizing a cut-off of > or = 10 mm, the prevalence was 11.4%. Irrespective of cut-off, the Monotest showed a sensitivity of > 90% and a specificity of > 80%. At a prevalence of 25.7%, and with cut-offs of > or = 5 or > or = 10 mm, the positive predictive value was 83% or 62.2%, respectively. Irrespective of cut-off, the negative predictive value was > 97%. In conclusion, the Monotest proved satisfactory as a tool for epidemiological screening in a population with a high prevalence for latent tuberculosis, namely drug users.

Compliance with hepatitis B vaccination in 1175 heroin users and risk factors associated with lack of vaccine response.

AIMS: To investigate the feasibility of hepatitis B vaccination among heroin users, assessing adherence to the vaccination schedules and identifying factors associated with antibody response. DESIGN AND PARTICIPANTS: A large cohort study in nine public centres for drug users (PCDUs) in north-eastern Italy, with data collected between January 1989 and December 1998. A total of 1175 heroin users were selected and vaccinated with a recombinant vaccine using two schedules (0-1-6 months and 0-1-2 months). FINDINGS: Eighty-eight per cent of patients completed the vaccination series and a protective antibody response occurred in 77% of subjects. Completion of the vaccination series was not related to the length of the vaccination schedule or whether the patient was still in drug abuse treatment at the end of the series, but was related strongly to the number of patients enrolled at each PCDU (Spearman correlation = - 0.93, P < 0.001). Four variables were significantly associated with lack of seroconversion in response to vaccination: older age (AOR = 0.91 per year, 95% CI 0.88-0.94, P < 0.001), 2-month vaccination schedule (AOR = 3.10, 95% CI 2.06-4.68, P < 0.001), HCV seropositivity (AOR = 0.69, 95% CI 0.47-0.99, P = 0.04), HIV seropositivity (AOR = 0.27, 95% CI 0.10-0.77, P = 0.01). CONCLUSIONS: A large-scale, multi-site hepatitis B vaccination programme for heroin users proved feasible and effective. The factors associated with a lack of antibody response may be useful in identifying patients who would benefit most from routine post-vaccination testing, with booster doses for non-responders. These results suggest that hepatitis B vaccination for drug users should become a routine public health practice.