The ethics of clinical and epidemiological research.

The global burden of tuberculosis (TB) demands that research be undertaken. The vulnerability of the populations most at risk for TB demands that such research be subject to ethical review to protect their rights and interests. In this brief article we cannot review the vast and important literature bearing on the ethics of clinical and epidemiological research and public health surveillance. Instead, we have focused on three questions that have been at the center of discussion and debate and which have special relevance for TB. First, we examine a question that has special bearing when wealthy nations or international organizations carry out research in poor countries: what does justice require in the post trial period? Second, we examine the question of how the principles of consent and confidentiality may require modification in record-based epidemiological research. Third, we look at the challenges posed by public health surveillance, which in many cases requires case reporting by clinicians to public health agencies. By way of conclusion, we take note of the centrality of enhancing the institutional capacities for ethical review of research in poor nations.

Drug resistance mutation profile and accumulation kinetics in human immunodeficiency virus-positive individuals infected with subtypes B and F failing highly active antiretroviral therapy are influenced by different viral codon usage patterns.

The major human immunodeficiency virus type 1 subtype circulating in Brazil is B, followed by F and C. We have genotyped 882 samples from Brazilian patients for whom highly active antiretroviral therapy failed, and we found subtype B and the unique recombinant B/F1 forms circulating. Due to codon usage variation, there is a significantly lower incidence of the substitutions L210W, Q151M, and F116Y in subtype F1 isolates than in the subtype B counterparts.

False I50V resistance readings of HIV isolates: co-amplification of NASBA HIV-1 RNA QT internal calibrators and HIV-1 patient isolates may lead to a false I50V mutation resistance reading in genotypic tests.

The I50V protease inhibitor (PI) resistance mutation was found in 87.4% of protease gene fragments sequenced from 199 nucleic acid isolates extracted using an NASBA virus load assay, performed between 1997 and 2001 in Brazil. This mutation is an amprenavir-related mutation, and at that particular time this PI was seldom used in Brazil. This mutation was found both in patients with and without therapeutic success. Q calibrators showed the PI resistance mutation I50V when directly amplified and sequenced from the 423-bp PCR product targeting protease gene. The majority of the patients' samples had a mixture of I50I and I50V; however, this artifact was nor seen when a 989-bp PCR product was used. These results show that RNA extracted using virus load kits need to be critically evaluated before being used in home-brew genotypic tests.

Autonomy and susceptibility to HIV/AIDS among young women living in a slum in Belo Horizonte, Brazil.

In Brazil in the last decade there has been an increase in the susceptibility of young women to HIV. This study explored the link between autonomy, or control over major domains of economic, social and sexual life, and susceptibility to HIV infection among poor young women living in an urban slum area of Brazil. A cross-sectional survey was carried out on a random sample of 356 young women between 15 and 24 years old. The study found that indicators of autonomy that relate to sexuality, mobility and freedom from threat by partners were significantly correlated with practices linked to HIV prevention and with access to health services promoting prevention, especially among adolescents. Young women who talked to their partner about condom use before first intercourse and co-decided with them on condom use were more likely to use condoms. In contrast, those who had ever been victim of physical violence by a partner or whose partners restricted their mobility were less likely to use condoms. The study found that young women were more likely to have accessed health services for gynaecological examinations, family planning services and HIV testing if they had ever been pregnant. The findings indicate that structural gender inequalities translate into unequal relationships and reduced autonomy, increasing young women's susceptibility to HIV. A bias in HIV testing and reproductive health services towards pregnant women leaves many susceptible youth without early access. The study suggests the development of a reproductive health policy that ensures that young women access services before they get pregnant and that also reaches young males.

[Assessment of the compliance to antiretroviral drugs among HIV/AIDS patients]. / Avaliação da aderência aos anti-retrovirais em pacientes com infecção pelo HIV/Aids.

OBJECTIVES: To assess the compliance to antiretroviral drugs, and identify the main predictive factors and causes for treatment failure and poor compliance. METHODS: Twenty HIV/AIDS were randomly selected for the study. The assessment was carried out using self-reporting and complemented with diary and pharmacy checks. Univariate analysis was performed using Student test and Qui-square. Odds ratio was calculated as an inclusion measure. RESULTS: One hundred and twenty patients were assessed, of which 87 (72.5%) were males and 33 (27.5%) were females, with a mean age of 35.5 years old. Most of them were light dark skin, had completed only elementary school, and were employed, with an income of up to two minimum wages. The mean time of the antiretroviral use was 12 months. The main reason to initiate treatment was a decrease in CD4 lymphocyte counts to less than 350 cells/mm3. Most were taking three or more antiretrovirals. Eighty-nine patients (74%) were considered compliant. The main cause of treatment failure was the medication side effects. The educational level, age and time of antiretroviral use were the most important predictors of compliance to antiretrovirals. CONCLUSIONS: To improve treatment compliance there is a need to have treatment regimens with less side effects and treatment all the aspects should be constantly reviewed.

Design, implementation, and evaluation at entry of a prospective cohort study of homosexual and bisexual HIV-1-negative men in Belo Horizonte, Brazil: Project Horizonte.

BACKGROUND AND OBJECTIVES: Project Horizonte, an open cohort of homosexual and bisexual HIV-1-negative men, is a component of the Minas Gerais AIDS Vaccine Program of the Federal University of Minas Gerais, Belo Horizonte, Brazil. Its objectives included the evaluation of seroincidence of HIV, to ascertain the role of counseling on behavior modification and to assess their willingness to participate in future HIV vaccine trials. METHODS: Various means of recruitment were used, including pamphlets, notices in community newspapers, radio, and television, at anonymous testing centers, and by word of mouth. RESULTS: From October 1994 to May 1999, 470 volunteers were enrolled. Their mean age was 26 years and over 70% of them had high school or college education. During the follow-up, they were seen every 6 months, when they received counseling and condoms, and when HIV testing was done. Eighteen seroconversions were observed, and the incidence rates estimates were 1.75 per 100 and 1.99 per 100 person-years, for 36 and 48 months of follow-up, respectively. During the entire period, 139 volunteers were lost to follow-up. Among them, 59 (42.4%) never returned after the initial visit and 51 (36.7) came only once after their initial visit. No losses were observed for those observed during follow-up for more than 3 years. At enrollment, 50% of participants said they would participate in a vaccine trial, and 30% said they might participate. CONCLUSIONS: The results obtained up to this moment confirm the feasibility of following this type of cohort for an extended period, estimating HIV incidence rate, and evaluating counseling for safe sexual practices in preparation for clinical trials with candidate HIV vaccines in Brazil.

Sexually transmitted diseases in homosexual and bisexual males from a cohort of human immunodeficiency virus negative volunteers (Project Horizonte), Belo Horizonte, Brazil

Sexually transmitted diseases (STD) are very frequent in the whole world. Males who do not use a condom during their sexual relations are at great risk. We report cases of STD during six months of observation, among homosexual/bisexual males who participate in the Project Horizonte. There were 16 cases of genital warts, 6 cases of human immunodeficiency virus infection, 24 cases of unspecific urethritis, 28 cases of herpes simplex virus infection, 30 cases of syphilis, 58 cases of gonorrhea and 84 cases of pediculosis. We concluded that a condom must be used in all sexual relations and new counseling techniques are needed, to avoid this situation

Sexually transmitted diseases in homosexual and bisexual males from a cohort of human immunodeficiency virus negative volunteers (Project Horizonte), Belo Horizonte, Brazil.

Sexually transmitted diseases (STD) are very frequent in the whole world. Males who do not use a condom during their sexual relations are at great risk. We report cases of STD during six months of observation, among homosexual/bisexual males who participate in the Project Horizonte. There were 16 cases of genital warts, 6 cases of human immunodeficiency virus infection, 24 cases of unspecific urethritis, 28 cases of herpes simplex virus infection, 30 cases of syphilis, 58 cases of gonorrhea and 84 cases of pediculosis. We concluded that a condom must be used in all sexual relations and new counseling techniques are needed, to avoid this situation.

Risk factors for tuberculosis among human immunodeficiency virus-infected persons. A case-control study in Belo Horizonte, Minas Gerais, Brazil (1985-1996).

The objective of this study was to identify tuberculosis risk factors and possible surrogate markers among human immunodeficiency virus (HIV)-infected persons. A retrospective case-control study was carried out at the HIV outpatient clinic of the Universidade Federal de Minas Gerais in Belo Horizonte. We reviewed the demographic, social-economical and medical data of 477 HIV-infected individuals evaluated from 1985 to 1996. The variables were submitted to an univariate and stratified analysis. Aids related complex (ARC), past history of pneumonia, past history of hospitalization, CD4 count and no antiretroviral use were identified as possible effect modifiers and confounding variables, and were submitted to logistic regression analysis by the stepwise method. ARC had an odds ratio (OR) of 3.5 (CI 95% - 1.2-10.8) for tuberculosis development. Past history of pneumonia (OR 1.7 - CI 95% 0.6-5.2) and the CD4 count (OR 0.4 - CI 0. 2-1.2) had no statistical significance. These results show that ARC is an important clinical surrogate for tuberculosis in HIV-infected patients. Despite the need of confirmation in future studies, these results suggest that the ideal moment for tuberculosis chemoprophylaxis could be previous to the introduction of antiretroviral treatment or even just after the diagnosis of HIV infection.

Fat malabsorption assessed by 14C-triolein breath test in HIV-positive patients in different stages of infection: is it an early event?

The aim of this study was to evaluate fat absorption in HIV-positive (HIV+) patients in different phases of HIV infection using a 14C-triolein breath test. We distributed 47 HIV+ patients according to the 1993 Centers for Disease Control Revised Classification: 20 in Group 2 (A1 or A2) and 27 in Group 3 (B1, B2, A3, B3, or C). Ten HIV-negative healthy subjects comprised the control group (Group 1). All individuals underwent a 14C-triolein breath test. Parasitic infection was evaluated through three stool exams, including Cryptosporidium and Isospora investigation. The median value of cumulative 6 hours' 14C excretion expressed as percentage of the 14C given as triolein was significantly higher in Group 1 (8.4%) than Group 2 (5.5%) or Group 3 (3.4%), p = 0.04 and p << 0.01, respectively. Fat malabsorption was found in 25% of Group 2 individuals, 52.6% of those without diarrhea in Group 3, and was correlated with CD4+ lymphocyte counts (p << 0.01). Fat malabsorption is a common feature in advanced stages of HIV infection, even in the absence of diarrhea and is also present in asymptomatic HIV+ patients. These findings suggest that malabsorption is an early event in HIV-infected individuals and is correlated with the degree of immunosuppression.

Revising the declaration of Helsinki: ethics vs economics or the fallacy of urgency.

Constant vigilance is required to ensure that the rights of volunteers in clinical trials are protected, particularly in developing countries. In this presentation to the XIII International AIDS Conference (abstract ThOrE651), Dirceu B Greco, of the Federal University of Minas Gerais in Brazil, describes the debate that has raged over the proposed changes to the Declaration of Helsinki, particularly with respect to access to medical care for trial volunteers and to the use of placebos in the control arms of the trials. The presentation argues: (1) that all trial volunteers should have access to the best diagnostic, preventive, and therapeutic methods, regardless of the standard of care in the countries where the trials are taking place; (2) that large efficacy trials of vaccines and drugs should be done first in countries where the best diagnostic, preventive, and therapeutic methods are available; and (3) that the costs of providing care and prevention services should be considered an integral part of the cost of the trials. The presentation explains how a partnership between activists, scientists, ethicists, and medical associations was effective in resisting pressures to lower the ethical standards for clinic trials. The presentation concludes that the gains made by this partnership constitute an important step in the struggle to provide universal access to education and health.

[Dynamics of institutionalization of older adults in Belo Horizonte, Brazil]. / Dinâmica da institucionalização de idosos em Belo Horizonte, Brasil.

INTRODUCTION: Epidemiological and social changes related to population aging in Brazil will probably increase the need for nursing homes (NH). The study analyses the dynamics of institutionalization in Belo Horizonte, a 3 million inhabitant city of whom 8.0% are aged 60 or more. METHODS: Age and length of stay of 1,128 NH residents (92.5% of the estimated population) was registered and occupancy and institutionalization rates were determined. RESULTS: Among women aged 65+ in Belo Horizonte, 0.88% were living in NH; among men, 0.26%. Occupancy rates were 92%. Women (81%) were older than men (76.4 x 70.4 years; two-tailed t test = 6. 4; p=0.00) and lived there for a longer period (5.6 x 4.5 years; two-tailed t test = 2.6; p=0.01). Almost 1/3 of the men were aged < 65. CONCLUSIONS: High occupancy rates, long waiting lists and hard criteria for admission (half reject demented or dependent individuals) insinuates that these low institutionalization rates are related to scarcity of beds. The preponderance of women reflects the proportion of those widowed or separated in the community (66% of those aged 65-+, versus 76% of married man). The high frequency of institutionalized men aged <65 suggests lower capacity of maintaining themselves after widowhood. High death rates (24% during a 20 month follow-up of a 263 random sample) determines the small median length of stay (3 years). These data unveil the anachronism of a system which is not directed towards the maintenance of the Brazilian older people among their families and homes.

[Knowledge, attitudes, and practice regarding occupational risk of exposure to HIV among medical students at the Medical School of the Federal University of Minas Gerais]. / Conhecimento, atitudes e comportamentos frente ao risco ocupacional de exposição ao HIV entre estudantes de Medicina da Faculdade de Medicina da Universidade Federal de Minas Gerais.

The objectives of this study were to evaluate the occupational risk of medical students, their knowledge and practice of universal biosafety measures and hepatitis B immunization coverage. A specific questionnaire was applied to 136 medical students of the Universidade Federal de Minas Gerais: 87 (64%) students were involved in surgical procedures, 68 (50%) had been exposed to blood, 90 (66.2%) knew the universal biosafety measures and 33 (24.3%) knew the procedure in case of blood exposure. Thus, this population has a high risk of blood exposure and although there is a low formal knowledge about universal biosafety measures, most of these were generally used. New strategies, such as formal teaching of universal biosafety measures, in loco supervision, and biosafety teams, are necessary to change this situation.

Pathogenetic factors of acute schistosomiasis mansoni: correlation of worm burden, IgE, blood eosinophilia and intensity of clinical manifestations.

A clinical study of 34 previously healthy young patients simultaneously infected in an endemic area of schistosomiasis mansoni is presented, emphasizing the initial phase of the infection. Its intensity was established according to the occurrence, intensity, and duration of the signs and symptoms in order to investigate the possible correlations between the worm burden (estimated by the number of eggs in faeces), the blood eosinophilia and specific levels of IgE (estimated by the area of immediate intradermal reaction), with the clinical manifestations. A significant but low-level association was found between the worm burden and morbidity, suggesting that multiple factors, besides worm burden itself, may contribute to the pathogenesis of the disease.

Secondary cutaneous manifestations of acute schistosomiasis mansoni.

The secondary cutaneous manifestations of the initial phase of schistosomiasis mansoni were studied in 34 patients who had been infected simultaneously in the same location. Sixteen of the patients developed angioedema and/or urticaria, generally of short duration and of mild intensity and usually about 30 days post-infection. There was no apparent association between the occurrence of these skin manifestations and the patients' worm burdens, blood eosinophilias or areas of immediate reaction to an intradermal inoculation with worm antigen. Other factors, particularly host immunological reactivity, are thought to be important elements in the genesis of the manifestations.

Pulmonary manifestations in the initial phase of schistosomiasis mansoni.

The clinical and radiological pulmonary manifestations in the initial phase of schistosomiasis mansoni were studied in thirty previously healthy individuals who were simultaneously infected. The findings were compared with those concerning a control group and related to possible pathogenetic factors. The respiratory manifestations were of light or of moderate intensity, the dry cough being the most common symptom. The significant radiological alterations were: thickening of bronchial walls and beaded micronodulation, predominantly localized in the lower pulmonary fields. It was observed significant association between wheezing and IgE levels, estimated by the area of immediate intradermal reaction, as well as between the number of blood eosinophils and the occurrence of radiological changes. Moreover, there was correlation between the worm burden and the presence of wheezing, thoracic pain and beaded micronodulation. Thus, the clinical and radiological pulmonary manifestations described are significant part of the initial phase of schistosomiasis mansoni and present the worm burden, eosinophilia and levels of IgE as probable pathogenetic factors.

Gastro-intestinal manifestations of the initial phase of schistosomiasis mansoni.

Clinical gastro-intestinal manifestations were studied in 34 patients in the initial phase of schistosomiasis mansoni. The patients, all men, were of similar age and in similar nutritional condition and had been infected simultaneously at the same transmission site. Most (85%) showed some gastro-intestinal sign or symptom, generally of light or moderate intensity; 56% had liquid or pasty diarrhoea, 41% abdominal pain, 29% hepatomegaly, 21% dysentery, 15% anorexia, 12% pain on colon palpation and 9% nausea and/or vomiting. High worm burden was associated with blood in faeces but apparently not with any other clinical manifestation. There was no apparent association between any clinical manifestation and peripheral-blood eosinophil counts or titres of IgE specific for Schistosoma mansoni (evaluated by the area of immediate intradermal reaction to injected adult worm antigen). The absence of association between worm burden and nearly all the clinical gastro-intestinal manifestations strengthens the concept that factors other than worm burden, such as host reactivity, constitute important pathogenetic elements in the initial phase of schistosomiasis mansoni.

HIV risk behavior and medical status of underprivileged youths in Belo Horizonte, Brazil.

METHODS: From June 1989 to April 1991, 394 adolescents aged 10-18 years randomly selected upon admission at a state shelter in Belo Horizonte, Brazil underwent health history interview, physical examination, serology for HIV, hepatitis B, and syphilis, and stool examination. Participants were classified as street-based youths (n = 195) or home-based youths (n = 199). The age distribution was similar in both groups, although males were overrepresented among street-based youths (79.5% versus 62.3%). RESULTS: Compared with home-based youths, street-based youths reported earlier onset (p = 0.009) and higher rates of sexual activity (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.4-3.3), sexual abuse (OR, 3.7; 95% CI, 1.2-10.1), and sexually transmitted diseases (OR, 2.9; 95% CI, 1.3-6.6). Overall condom use was low in both groups. Street-based youths were 7.8 times more likely to use drugs than home-based youths (95% CI, 4.9-12.7). Inhalants and marijuana were the more commonly used drugs. Intravenous drug use was low. CONCLUSIONS: Although chronic malnutrition and multiple parasitosis were common findings in both groups, street-based youths were more likely to present disorders related to trauma and poor hygienic conditions. Antibodies to HIV were detected in four (2%) street-based youths and in none of the home-based youths. This study confirms that street youths are at higher risk for HIV infection than their home-based peers and indicates a need for HIV prevention programs targeting this population.