Sayonara Rocha Ribeiro

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.

Survival of AIDS patients using two case definitions, Rio de Janeiro, Brazil, 1986-2003

Background:Recent studies have shown substantial increases in the survival of AIDS patients in developed countries and in Brazil as a result of antiretroviral therapy (ART) and prophylaxis for opportunistic infections. This study compares survival rates using the Brazilian Ministry of Health 2004 and Centers for Disease Control and Prevention (CDC) 1993 case definitions in a large HIV/AIDS referral centre in Rio de Janeiro. Methods:Survival after AIDS diagnosis was assessed in a clinic-based cohort of 1415 individuals using the Kaplan–Meier method and Cox proportional hazards models. Results:There were 393 (88%) deaths from AIDS-related causes and 52 (12%) from unrelated or unknown causes. A total of 205 patients (14%) were lost to follow-up and 765 patients (55%) remained alive until the end of the study. Three-quarters of patients (75%) were still alive 22 months [95% confidence interval (CI) 19–26] after the AIDS diagnosis according to the CDC case definition and 31 months (95% CI 26–36) according to the Ministry of Health case definition. Independent predictors of survival included AIDS defined by CD4 cell count and any use of highly active antiretroviral therapy, with either case definition, and initial stage of the case, with the Ministry of Health case definition. Conclusion:Survival observed in this reference centre is comparable or longer than other international studies, although the choice of case definition criterion influenced findings. Adoption of the Ministry of Health case definition may enhance the ability to track the use of and outcomes from ART among AIDS patients.

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.

HIV and cancer: a comparative retrospective study of Brazilian and U.S. clinical cohorts

BackgroundWith successful antiretroviral therapy, non-communicable diseases, including malignancies, are increasingly contributing to morbidity and mortality among HIV-infected persons. The epidemiology of AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs) in HIV-infected populations in Brazil has not been well described. It is not known if cancer trends in HIV-infected populations in Brazil are similar to those of other countries where antiretroviral therapy is also widely available.MethodsWe performed a retrospective analysis of clinical cohorts at Instituto Nacional de Infectologia Evandro Chagas (INI) in Rio de Janeiro and Vanderbilt Comprehensive Care Clinic (VCCC) in Nashville from 1998 to 2010. We used Poisson regression and standardized incidence ratios (SIRs) to examine incidence trends. Clinical and demographic predictors of ADCs and NADCs were examined using Cox proportional hazards models.ResultsThis study included 2,925 patients at INI and 3,927 patients at VCCC. There were 57 ADCs at INI (65% Kaposi sarcoma), 47 at VCCC (40% Kaposi sarcoma), 45 NADCs at INI, and 82 at VCCC. From 1998 to 2004, incidence of ADCs remained statistically unchanged at both sites. From 2005 to 2010, ADC incidence decreased in both cohorts (INI incidence rate ratio per year = 0.74, p < 0.01; VCCC = 0.75, p < 0.01). Overall Kaposi sarcoma incidence was greater at INI than VCCC (3.0 vs. 1.2 cases per 1,000 person-years, p < 0.01). Incidence of NADCs remained constant throughout the study period (overall INI incidence 3.6 per 1,000 person-years and VCCC incidence 5.3 per 1,000 person-years). Compared to general populations, overall risk of NADCs was increased at both sites (INI SIR = 1.4 [95% CI 1.1-1.9] and VCCC SIR = 1.3 [1.0-1.7]). After non-melanoma skin cancers, the most frequent NADCs were anal cancer at INI (n = 7) and lung cancer at VCCC (n = 11). In multivariate models, risk of ADC was associated with male sex and immunosuppression. Risk of NADC was associated with increased age.ConclusionsIn both cohorts, ADCs have decreased over time, though incidence of KS was higher at INI than VCCC. Rates of NADCs remained constant over time at both sites.

Incidence of virological failure and major regimen change of initial combination antiretroviral therapy in the Latin America and the Caribbean: an observational cohort study

BACKGROUND Access to combination antiretroviral therapy (ART) is expanding in Latin America (Mexico, Central America, and South America) and the Caribbean. We assessed the incidence of and factors associated with regimen failure and regimen change of initial ART in this region. METHODS This observational cohort study included antiretroviral-naive adults starting ART from 2000 to 2014 at sites in seven countries throughout Latin America and the Caribbean. Primary outcomes were time from ART initiation until virological failure, major regimen modification, and a composite endpoint of the first of virological failure or major regimen modification. Cumulative incidence of the primary outcomes was estimated with death considered a competing event. FINDINGS 14,027 patients starting ART were followed up for a median of 3.9 years (2.0-6.5): 8374 (60%) men, median age 37 years (IQR 30-44), median CD4 count 156 cells per μL (61-253), median plasma HIV RNA 5.0 log10 copies per mL (4.4-5.4), and 3567 (28%) had clinical AIDS. 1719 (12%) patients had virological failure and 1955 (14%) had a major regimen change. Excluding the site in Haiti, which did not regularly measure HIV RNA, cumulative incidence of virological failure was 7.8% (95% CI 7.2-8.5) 1 year after ART initiation, 19.2% (18.2-20.2) at 3 years, and 25.8% (24.6-27.0) at 5 years; cumulative incidence of major regimen change was 5.9% (5.3-6.4) at 1 year, 12.7% (11.9-13.5) at 3 years, and 18.2% (17.2-19.2) at 5 years. Incidence of major regimen change at the site in Haiti was 10.7% (95% CI 9.7-11.6) at 5 years. Virological failure was associated with younger age (adjusted hazard ratio [HR] 2.03, 95% CI 1.68-2.44, for 20 years vs 40 years), infection through injection drug use (vs infection through heterosexual sex; 1.60, 1.02-2.52), and initiation in earlier calendar years (1.28, 1.13-1.46, for 2002 vs 2006), but was not significantly associated with boosted protease inhibitor-based regimens (vs non-nucleoside reverse transcriptase inhibitor; 1.17, 1.00-1.36). INTERPRETATION Incidence of virological failure in Latin America and the Caribbean was generally lower than that reported in North America or Europe. Our results suggest the need to design strategies to reduce failure and major regimen change in young patients and those with a history of injection drug use. FUNDING US National Institutes of Health.

Mortality in HIV-infected women, heterosexual men, and men who have sex with men in Rio de Janeiro, Brazil: an observational cohort study

Background Mortality among HIV-infected individuals may differ by sex and mode of HIV acquisition. We studied mortality among women, heterosexual men, and men who have sex with men (MSM) in a cohort from Rio de Janeiro, Brazil. Methods HIV-infected adults followed at Instituto Nacional de Infectologia Evandro Chagas from 2000–2011 were included. Cox proportional hazards models accounting for competing risks were used to explore risk factors for AIDS and non-AIDS related deaths. Findings 2224 individuals were included (36·7%[817/2224] women, 24·9%[554/2224] heterosexual men, and 38·4%[853/2224] MSM). Throughout the study period, 103 deaths occurred: 64 due to AIDS-related causes, 31 due to non-AIDS related causes and 8 of unknown causes. In unadjusted analyses, compared to women, hazard of AIDS-related deaths was higher for heterosexual men (hazard ratio [HR] 3·52, 95% confidence interval [95%CI] 1·30–9·08) and for MSM (HR 2·30, 95%CI 0·89–5·94). After adjusting for confounders, excess risk of AIDS-related death observed for heterosexual men was attenuated (aHR 1·99, 95%CI 0·75–5·25, p-value=0.163), but unchanged for MSM (aHR 2·24, 95%CI 0·82–6·11, p-value=0.114). Non-AIDS related mortality did not differ by group. Interpretation Compared to women, increased risk of AIDS-related death among heterosexual men was partially mitigated by risk factors for AIDS mortality while excess risk observed among MSM was unchanged. Further study of reasons for AIDS-related mortality disparity by mode of transmission is needed.

Multi-state models for defining degrees of chronicity related to HIV-infected patient therapy adherence

Poucos estudos sobre AIDS que avaliam fatores associados a falha terapeutica consideram sua evolucao lenta, com a passagem por multiplos estados de saude, consequencia do uso de antirretrovirais. Nesse artigo foram estudados fatores associados a progressao entre estados imunes, enfocando adesao, em 722 pacientes HIV+ acompanhados por 3 anos. O desfecho foi a contagem de celulas CD4 classificada em s1 (CD4 ≥ 500), s2 (350 ≤ CD4 < 500) e s3 (CD4 < 350). As transicoes entre estados foram modeladas por modelos multiestado. A adesao a terapia antirretroviral e o tempo de doenca estao associados diferentemente a mudanca do estado imune vivido pelo paciente. Baixa adesao a terapia aumentou o risco de s1→s2 e adesao intermediaria aumentou o de s2→s3. Por outro lado, idades elevadas e tempo de doenca de 2 a 4 anos se apresentam como fatores de protecao na progressao da AIDS. A modelagem multiestado e uma abordagem poderosa no estudo de doencas cronicas, por estimar os fatores associados a cada etapa da evolucao de doencas cronicas, possibilitando a adocao de intervencoes mais individualizadas e eficazes.Few studies on AIDS that evaluate factors associated with treatment failure have considered the slow evolution of the disease and multiple health state transitions following the use of antiretrovirals. In this article we study factors associated with the progression between different stages of the disease, focusing on therapy adherence using a sample of 722 HIV+ patients followed up for 3 years. States were defined using the following classifications of the CD4 cell count: s₁ (CD4 ≥ 500); s₂ (350 ≤ CD4 < 500); and s₃ (CD4 < 350). The transitions between states were modeled using multi-state models. Antiretroviral therapy adherence and disease duration were associated with transitions between immune states during follow-up. Low adherence increased the hazard ratio of a transition between s₁ to s₂ and intermediate adherence increased the hazard ratio of a transition between s₂ to s₃. On the other hand, older age and disease duration between two and four years are protective factors for AIDS progression. Multi-state modeling is a powerful approach for studying chronic diseases and estimating factors associated with transitions between each stage of progression, thus enabling the use of more individualized and effective interventions.

Hospitalization rates, length of stay and in-hospital mortality in a cohort of HIV infected patients from Rio de Janeiro, Brazil

In this study, we evaluated trends in hospitalization rates, length of stay and in-hospital mortality in a cohort of HIV-infected patients in Rio de Janeiro, Brazil, from 2007 through 2013. Among the 3991 included patients, 1861 hospitalizations occurred (hospitalization rate of 10.44/100 person-years, 95% confidence interval 9.98–10.93/100 person-years). Hospitalization rates decreased annually (per year incidence rate ratio 0.92, 95% confidence interval 0.89–0.95) as well as length of stay (median of 15 days in 2007 vs. 11 days in 2013, p-value for trend < 0.001), and in-hospital mortality (13.4% in 2007 to 8.1% in 2013, p-value for trend = 0.053). Our results show that, in a middle-income setting, hospitalization rates are decreasing over time and non-AIDS hospitalizations are currently more frequent than those related to AIDS. Notwithstanding, compared with high-income settings, our patients had longer length of stay and higher in-hospital mortality. Further studies addressing these outcomes are needed to provide information that may guide protocols and interventions to further reduce health-care costs and in-hospital mortality.

Diabetes Mellitus is Associated with Increased Death Rates Among HIV-Infected Patients in Rio de Janeiro, Brazil.

Diabetes mellitus (DM) is a major cause of morbidity worldwide and a known factor leading to increased risk of death, especially in conjunction with other risk factors. In this study, we evaluated the prevalence of DM among HIV-infected patients and its association with overall mortality. All HIV-infected patients 18 years or older who were followed in the Instituto Nacional de Infectologia Evandro Chagas (INI) cohort from January 1991 to December 2011 were included. Time-updated covariables included DM status, calendar year, combination antiretroviral therapy (cART), and CD4 cell counts. Fixed demographic covariables included gender and age at entry. Poisson models were used to calculate mortality rate ratios (RR) with robust variances. Among the 4,871 patients included, 1,192 (24.4%) died (mortality rate = 4.72/100 person-years [PY]; 95% confidence interval [CI] = 4.46-5.00). Death rates were significantly higher among those presenting with DM compared with those who did not (6.16/100 vs. 4.61/100 PY, respectively. p = 0.001). In the final model, DM was significantly associated with mortality (RR = 1.74; 95% CI = 1.57-1.94; p < 0.001). When the analysis was restricted to those on cART or the period post-1996, the association between DM and mortality was even stronger (RR = 2.17; 95% CI = 1.91-2.46; p < 0.001 and RR = 1.95; 95% CI = 1.75-2.18; p < 0.001, respectively). Among the major groups of cause of deaths (CODs), the proportion of AIDS-related conditions in patients with DM was lower (74.27% vs. 58.93%, respectively; p < 0.001); whereas in non-AIDS-related conditions, nonimmunodeficiency-related causes (22.44% vs. 34.82%, respectively; p = 0.004) were more common in patients with DM. In conclusion, DM was associated with increased mortality rates even after controlling for HIV-related variables associated to this outcome. Differences in the underlying CODs were identified, reinforcing the necessity to assess and treat comorbidities such as DM in HIV-infected patients.Abstract Diabetes mellitus (DM) is a major cause of morbidity worldwide and a known factor leading to increased risk of death, especially in conjunction with other risk factors. In this study, we evaluated the prevalence of DM among HIV-infected patients and its association with overall mortality. All HIV-infected patients 18 years or older who were followed in the Instituto Nacional de Infectologia Evandro Chagas (INI) cohort from January 1991 to December 2011 were included. Time-updated covariables included DM status, calendar year, combination antiretroviral therapy (cART), and CD4 cell counts. Fixed demographic covariables included gender and age at entry. Poisson models were used to calculate mortality rate ratios (RR) with robust variances. Among the 4,871 patients included, 1,192 (24.4%) died (mortality rate = 4.72/100 person-years [PY]; 95% confidence interval [CI] = 4.46–5.00). Death rates were significantly higher among those presenting with DM compared with those who did not (6.16/100 vs. 4.61/...

Effects of antiretroviral treatment and nadir CD4 count in progression to cardiovascular events and related comorbidities in a HIV Brazilian cohort: a multi-stage approach

ABSTRACT The use of highly active antiretroviral therapy has resulted in changes of comorbidity profile in people living with HIV (PLHIV), increasing non-AIDS-related events. The occurrence of cardiovascular events is greater in PLHIV, but the mechanism responsible for it is still controversial. This article aimed to investigate factors associated with the progression to cardiovascular events in PLHIV using HAART. A 15-years cohort study with 1135 PLHIV was conducted in Rio de Janeiro-Brazil. Clinical progression was stratified in five states: No comorbidities (s1), arterial hypertension (s2), lipid abnormalities (s3), hypertension and lipid abnormalities (s4) and major cardiovascular events (stroke, coronary artery disease, thrombosis or death) (s5). Semi-Markov models evaluated the effects of cardiovascular traditional factors, treatment and clinical covariates on transitions between these states. Hazard Ratios (HR) and 95% confidence intervals (CI) were provided. In addition to traditional factors (age, sex, educational level and skin color), the development of one comorbidity (lipid abnormalities or hypertension) increased in patients with low nadir CD4 (<50 cells/mm3), (HR = 1.59, CI 1.11–2.28 and 1.36, CI 1.11–1.66, respectively). The risk to experience a second comorbidity (s3→s4) increased 75% with low nadir CD4. Age was the only factor that increased the risk of major cardiovascular events once having lipid abnormalities with or without hypertension (s3,s4→s5). The prolonged use of certain antiretroviral drugs (abacavir, didanosine, ritonavir, lopinavir, amprenavir and fosamprenavir) increased the risk of direct transition (s1→s5) to major cardiovascular events (HR = 5.29, CI 1.16–24.05). This analysis suggests that prolonged use of certain antiretroviral drugs led directly to major cardiovascular events, while low nadir CD4 only affected the occurrence of lipid abnormalities and hypertension. Management strategies, including rational use of complex exams (such as, computed-tomography angiography), statins and antihypertensives, should be developed based on the distinct roles of antiretroviral use and of HIV infection itself on the progression to cardiovascular events.