Ronaldo I. Moreira

Changing Mortality Profile among HIV-Infected Patients in Rio de Janeiro, Brazil: Shifting from AIDS to Non-AIDS Related Conditions in the HAART Era

Introduction We describe temporal trends in the mortality rates and factors associated with AIDS and non-AIDS related mortality at the Evandro Chagas Clinical Research Institute (IPEC), Oswaldo Cruz Foundation (FIOCRUZ). Methods Adult patients enrolling from 1986 through 2009 with a minimum follow up of 60 days were included. Vital status was exhaustively checked using patients’ medical charts, through active contact with individuals and family members and by linkage with the Rio de Janeiro Mortality database using a previously validated algorithm. The CoDe protocol was used to establish the cause of death. Extended Cox proportional hazards models were used for multivariate modeling. Results A total of 3530 individuals met the inclusion criteria, out of which 868 (24.6%) deceased; median follow up per patient was 3.9 years (interquartile range 1.7–9.2 years). The dramatic decrease in the overall mortality rates was driven by AIDS-related causes that decreased from 9.19 deaths/100PYs n 1986–1991 to 1.35/100PYs in 2007–2009. Non-AIDS related mortality rates remained stable overtime, at around 1 death/100PYs. Immunodeficiency significantly increased the hazard of both AIDS-related and non-AIDS-related causes of death, while HAART use was strongly associated with a lower hazard of death from either cause. Conclusions Our results confirm the remarkable decrease in AIDS-related mortality as the HIV epidemic evolved and alerts to the conditions not traditionally related to HIV/AIDS which are now becoming more frequent, needing careful monitoring.

Early mortality and cause of deaths in patients using HAART in Brazil and the United States.

Objective:To compare the early mortality pattern and causes of death among patients starting HAART in Brazil and the United States. Methods:We analyzed the combined data from two clinical cohorts followed at the Johns Hopkins AIDS Service in Baltimore, United States, and the Evandro Chagas Clinical Research Institute AIDS Clinic in Rio de Janeiro, Brazil. Participants included those who entered either cohort between 1999 and 2007 and were antiretroviral naive. Follow-up was at 1 year since HAART initiation. Cox proportional hazards regression analysis was used to assess the role of the city on the risk of death. Results:A total of 859 and 915 participants from Baltimore and Rio de Janeiro, respectively, were included. In Rio de Janeiro, 64.7% of deaths occurred within 90 days of HAART initiation; in Baltimore, 48.9% occurred between 180 and 365 days. AIDS-defining illness (61.8%) and non-AIDS-defining illness (55.6%) predominated as causes of death in Rio de Janeiro and Baltimore, respectively. Risk of death was similar in both cities (hazard ratio 1.04; P value = 0.95) after adjusting for CD4+ T cell count, age, sex, HIV risk group, prior AIDS-defining illness, and Pneumocystis jirovecii pneumonia and Mycobacterium avium prophylaxis. Individuals with CD4+ T cell count less than or equal to 50 cells/μl (hazard ratio 4.36; P = 0.001) or older (hazard ratio, 1.03; P = 0.03) were more likely to die. Conclusion:Although late HIV diagnosis is a problem both in developed and developing countries, differences in the timing and causes of deaths clearly indicate that, besides interventions for early HIV diagnosis, different strategies to curb early mortality need to be tailored in each country.

Factors associated with increased prevalence of human papillomavirus infection in a cohort of HIV-infected Brazilian women

OBJECTIVES Human papillomavirus (HPV) infection is a major risk factor for cervical disease. Using baseline data from the HIV-infected cohort of Evandro Chagas Clinical Research Institute at Fiocruz, Rio de Janeiro, Brazil, factors associated with an increased prevalence of HPV were assessed. METHODS Samples from 634 HIV-infected women were tested for the presence of HPV infection using hybrid capture II and polymerase chain reaction. Prevalence ratios (PR) were estimated using Poisson regression analysis with robust variance. RESULTS The overall prevalence of HPV infection was 48%, of which 94% were infected with a high-risk HPV. In multivariate analysis, factors independently associated with infection with high-risk HPV type were: younger age (<30 years of age; PR 1.5, 95% confidence interval (CI) 1.1-2.1), current or prior drug use (PR 1.3, 95% CI 1.0-1.6), self-reported history of HPV infection (PR 1.2, 95% CI 0.96-1.6), condom use in the last sexual intercourse (PR 1.3, 95% CI 1.1-1.7), and nadir CD4+ T-cell count <100cells/mm(3) (PR 1.6, 95% CI 1.2-2.1). CONCLUSIONS The estimated prevalence of high-risk HPV-infection among HIV-infected women from Rio de Janeiro, Brazil, was high. Close monitoring of HPV-related effects is warranted in all HIV-infected women, in particular those of younger age and advanced immunosuppression.

Immune status at presentation for HIV clinical care in Rio de Janeiro and Baltimore.

Background:Late presentation to HIV clinical care increases individual risk for (multiple) clinical events and death, and decreases successful response to highly active antiretroviral therapy (HAART). In Brazil, provision of HAART free of charge to all individuals infected with HIV could lead to increased testing and linkage to care. Methods:We assessed the immune status of 2555 patients who newly presented for HIV clinical care between 1997 and 2009 at the Johns Hopkins Clinical Cohort, in Baltimore, Md, and at the Instituto de Pesquisa Clinica Evandro Chagas Clinical Cohort, in Rio de Janeiro, Brazil. The mean change in the CD4 cell count per year was estimated using multivariate linear regression models. Results:Overall, from 1997 to 2009, 56% and 54% of the patients presented for HIV clinical care with CD4 count ≤350 cells per cubic millimeter in Baltimore and Rio de Janeiro, respectively. On average, 75% of the patients presented with viral load >10,000 copies per millimeter. In Rio de Janeiro only, the overall adjusted per year increase in the mean CD4 cell count was statistically significant (5 cells/mm3, 95% confidence interval: 1 to 10 cells/mm3). Conclusions:We found that, over years, the majority of patients presented late, that is, with a CD4 count <350 cells per cubic millimeter. Our findings indicate that, despite the availability of HAART for more than a decade, and mass media campaigns stimulating HIV testing in both countries, the proportion of patients who start therapy at an advanced stage of the disease is still high.

Assessing sexually transmitted infections in a cohort of women living with HIV/AIDS, in Rio de Janeiro, Brazil

A cohort of 458 HIV-positive women under antiretroviral therapy has been followed at a reference hospital in Rio de Janeiro, Brazil. Most of them belong to impoverished social strata. Patients were screened for sexually transmitted infections (STIs) and gynaecologic conditions. Some STIs were found to be uncommon (e.g. chlamydial and gonococcal infections), while some conditions (bacterial vaginosis) and STIs, e.g. hepatitis B and human papilloma virus (HPV) infection, were found to be quite prevalent. The latter is of special concern, due to the high prevalence of HIV/HPV co-infection (∼51%) and its association with severe immunodeficiency, in a context of unacceptable high levels of uterine cancer and uneven gynaecological care. HIV-positive women are in need of comprehensive health services, including high-quality, regular, gynaecologic care in order to diagnose and treat lower genital tract infections and prevent the evolution of HPV-related lesions. Reproductive counselling should be a part of this approach.

Incidence of Modifying or Discontinuing First HAART Regimen and Its Determinants in a Cohort of HIV-Infected Patients from Rio de Janeiro, Brazil

Studies on the long-term safety and tolerability of HAART are scarce in developing countries. HAART has been universally available in Brazil since 1997, providing a unique opportunity to evaluate the incidence and risk factors for HAART discontinuation or modification. We analyzed retrospective data from 670 treatment-naive patients followed at the HIV cohort of Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation, in Rio de Janeiro, Brazil, who first received HAART between January 1996 and December 2006. Our four outcomes of interest were treatment failure (TF-MOD), short-term toxicity (ST-MOD), long-term toxicity (LT-MOD), and overall modification/discontinuation (MOD, composed of TF-MOD, ST-MOD, LT-MOD, and other reasons). Risk factors were assessed using Coxs proportional hazards regression. Incidences of MOD, ST-MOD, LT-MOD, and TF-MOD were 28.3, 24.0, 4.0, and 5.6 per 100 persons-years, respectively. MOD was observed in 69% of the patients; 40% of the MODs were toxicity related. The risk of MOD in the first year of treatment was 32% (95% CI: 28.3-35.5%); the median time from HAART initiation to MOD was 14 months (IQR: 3.0-29.5). The most frequent reasons for ST-MOD were gastrointestinal; women had a higher hazard for ST-MOD. Metabolic toxicity was the most frequent reason for LT- MOD, particularly dislipidemia and lipodystrophy. Increased hazard of TF-MOD was observed among those with lower CD4(+) lymphocyte counts (<200 cells/mm(3)). Our results indicate that toxicities can compromise adherence and thus impact future treatment options. This is especially relevant in the context of limited access to second and third line treatment regimens.

High Prevalence of Sexually Transmitted Diseases in Young Women Seeking HIV Testing in Rio de Janeiro, Brazil

Background and Objectives Few data are available on the prevalence of and risk factors for sexually transmitted diseases (STDs) other than HIV in Brazil. Goal The goal of this study was to determine the prevalence of HIV infection and other STDs in Brazilian women who seek HIV testing, investigate risk factors for these infections, and assess feasibility of screening in HIV test clinic settings. Study Design We conducted a cross-sectional study of 200 women, aged 14 to 29 years, who attended an HIV testing site in central Rio de Janeiro. Participants completed a questionnaire and received testing for HIV, syphilis, chlamydia, and gonorrhea. Results HIV and other STDs were common (HIV 8%, syphilis 6.5%, chlamydial infection 8%, and gonorrhea 9.5%). HIV was significantly associated with lower education and with having an HIV-infected partner. Other STDs were significantly associated with younger age at first intercourse, heavy alcohol consumption, and marijuana use. Conclusion STDs appear to be substantial health problems among young Brazilian women seeking HIV testing. HIV testing sites in Brazil should consider offering screening and treatment for STDs and substance abuse as part of their HIV prevention services.

Continuous Increase of Cardiovascular Diseases, Diabetes, and Non-HIV Related Cancers as Causes of Death in HIV-Infected Individuals in Brazil: An Analysis of Nationwide Data

Introduction After antiretroviral therapy (ART) became available, there was a decline in the number of deaths in persons infected with HIV. Thereafter, there was a decrease in the proportion of deaths attributed to opportunistic infections and an increase in the proportion of deaths attributed to chronic comorbidities. Herein we extend previous observations from a nationwide survey on temporal trends in causes of death in HIV-infected patients in Brazil. Methods We describe temporal trends in causes of death among adults who had HIV/AIDS listed in the death certificate to those who did not. All death certificates issued in Brazil from 1999 to 2011 and listed in the national mortality database were included. Generalized linear mixed-effects logistic models were used to study temporal trends in proportions. Results In the HIV-infected population, there was an annual adjusted average increase of 6.0%, 12.0%, 4.0% and 4.1% for cancer, external causes, cardiovascular diseases (CVD) and diabetes mellitus (DM), respectively, compared to 3.0%, 4.0%, 1.0% and 3.9%, in the non-HIV group. For tuberculosis (TB), there was an adjusted average increase of 0.3%/year and a decrease of 3.0%/year in the HIV and the non-HIV groups, respectively. Compared to 1999, the odds ratio (OR) for cancer, external causes, CVD, DM, or TB in the HIV group were, respectively, 2.31, 4.17, 1.76, 2.27 and 1.02, while for the non-HIV group, the corresponding OR were 1.31, 1.63, 1.14, 1.62 and 0.67. Interactions between year as a continuous or categorical variable and HIV were significant (p<0.001) for all conditions, except for DM when year was considered as a continuous variable (p = 0.76). Conclusions Non HIV-related co-morbidities continue to increase more rapidly as causes of death among HIV-infected individuals than in those without HIV infection, highlighting the need for targeting prevention measures and surveillance for chronic diseases among those patients.

Factors associated with colposcopy-histopathology confirmed cervical intraepithelial neoplasia among HIV-infected women from Rio De Janeiro Brazil.

Introduction Despite the availability of preventive strategies (screening tests and vaccines), cervical cancer continues to impose a significant health burden in low- and medium-resourced countries. HIV-infected women are at increased risk for infection with human papillomavirus (HPV) and thus development of cervical squamous intraepithelial neoplasia (CIN). Methods Study participants included HIV-infected women enrolling the prospective open cohort of Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation (IPEC/FIOCRUZ). At cohort entry, women were subjected to conventional Papanicolaou test, HPV-DNA test and colposcopy; lesions suspicious for CIN were biopsied. Histopathology report was based on directed biopsy or on specimens obtained by excision of the transformation zone or cervical conization. Poisson regression modeling was used to assess factors associated with CIN2+ diagnosis. Results The median age of the 366 HIV-infected women included in the study was 34 years (interquartile range: 28–41 years). The prevalence of CIN1, CIN2 and CIN3 were 20.0%, 3.5%, and 2.2%, respectively. One woman was found to have cervical cancer. The prevalence of CIN2+ was 6.0%. Factors associated with CIN2+ diagnosis in the multivariate model were age < years compared to ≥35 years (aPR  =  3.22 95%CI 1.23–8.39), current tobacco use (aPR  =  3.69 95%CI 1.54–8.78), nadir CD4 T-cell count <350 cells/mm3 when compared to ≥ 350 cells/mm3 (aPR  =  6.03 95%CI 1.50–24.3) and concomitant diagnosis of vulvar and/or vaginal intraepithelial lesion (aPR  =  2.68 95%CI 0.99–7.24). Discussion Increased survival through wide-spread use of highly active antiretroviral therapy might allow for the development of cervical cancer. In Brazil, limited cytology screening and gynecological care adds further complexity to the HIV-HPV co-infection problem. Integrated HIV care and cervical cancer prevention programs are needed for the prevention of cervical cancer mortality in this group of women.

Trends in AIDS-defining opportunistic illnesses incidence over 25 years in Rio de Janeiro, Brazil.

Objectives To assess the temporal trends in incidence of AIDS-defining opportunistic illnesses in an urban cohort of a middle-income country. Methods HIV infected patients aged ≥18 years at cohort entry were included in this analysis. We calculated incidence rates per 1000 persons-years of observation for the first opportunistic illness presented after cohort enrollment, from 1987 to 2012. Trends for overall and specific opportunistic illnesses were tested and incidence rate ratios for the most recent calendar period were calculated as the ratio between the incidence rate observed in the most recent period of the study (2009–2012) and the incidence rate observed in first period of the study (1987–1990). Results Overall, 3378 patients were included in this analysis; of which 1119 (33%) patients presented an opportunistic illness during follow up. Incidence rates of all opportunistic illnesses decreased over time, and the overall opportunistic illness incidence rates fell from 295.4/1000 persons-years in 1987–1990 to 34.6/1000 persons-years in 2009–2012. Tuberculosis, esophageal candidiasis, cerebral toxoplasmosis and Pneumocystis jirovecii pneumonia were the most incident opportunistic illnesses in the cohort. Tuberculosis had the highest incidence rate in the study period. The peak in tuberculosis incidence occurred in 1991–1993 (80.8/1000 persons-years). Cerebral toxoplasmosis was the third most incident opportunistic illness in the study, with a peak of incidence of 43.6/1000 persons-year in 1987–1990. Conclusions All opportunistic illnesses incidence rates decreased over the years but they still occur in an unacceptable frequency. Tuberculosis co-infection among HIV-infected persists as an important challenge for health care professionals and policy makers in our setting. Impressively high rates of cerebral toxoplasmosis were found suggesting that its incidence among HIV-infected is linked to the high prevalence of Toxoplasma gondii infection in the general population.