Lara E. Coelho

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.

Trends in overall opportunistic illnesses, Pneumocystis carinii pneumonia, cerebral toxoplasmosis and Mycobacterium avium complex incidence rates over the 30 years of the HIV epidemic: a systematic review

BACKGROUND The natural history of HIV infection has changed dramatically after the introduction of highly active antiretroviral therapy. Currently, opportunistic illnesses still represent a major cause of death and hospitalization in this population. In this study, we review the trends in opportunistic illnesses incidence rates and compare the results observed in high-income settings with that for low/middle-income settings, with special attention given to studies from Brazil. METHODS We systematically searched Pubmed, Web of Science, Lilacs and Google scholar for publications on HIV associated opportunistic illness. Studies reporting rates based on person-time for all opportunistic illnesses and/or the three opportunistic infections of interest, namely, Pneumocystis carinii pneumonia, cerebral toxoplasmosis, and Mycobacterium avium complex were included. RESULTS Significant reductions in the incidence rates were demonstrated for opportunistic illnesses overall and also for the specific opportunistic infections included in the present study, both in high and low/middle-income settings. Out of the 37 studies included in the present review, almost 70% were from high-income settings. All the studies conducted in low/middle-income settings were single center studies and four were from Brazil. We found no study from Brazil reporting annual incidence rates of opportunistic illnesses. CONCLUSIONS Opportunistic illnesses remain an important public health problem. To better guide health policies in low/middle-income settings, multicenter cohort studies should be encouraged. Studies from Brazil are urgently needed to assess the current burden of opportunistic illnesses in our population and to support the planning of HIV/AIDS health care services organization.

Screening for Decreased Glomerular Filtration Rate and Associated Risk Factors in a Cohort of HIV-Infected Patients in a Middle-Income Country

With the introduction of combined active antiretroviral therapy and the improved survival of HIV-infected patients, degenerative diseases and drug toxicity have emerged as long-term concerns. We studied the prevalence of decreased glomerular filtration rate (GFR) and associated risk factors in a cohort of HIV-infected patients from a middle-income country. Our cross-sectional study included all adult patients who attended an urban outpatient clinic in 2008. GFR was estimated using the CKD-EPI equation. The prevalence ratio (PR) of decreased GFR (defined as <60 mL/min/1.73 m2) was estimated using generalizing linear models assuming a Poisson distribution. We analyzed data from 1,970 patients, of which 82.9% had been exposed to ART. A total of 249 patients (12.6%) had a GFR between 60 and 89 mL/min/1.73 m2, 3.1% had a GFR between 30 and 59, 0.3% had a GFR between 15 and 29, and 0.4% had a GFR <15. Decreased GFR was found in only 74 patients (3.8%). In the multivariate regression model, the factors that were independently associated with a GFR below 60 mL/min/1.73 m2 were as follows: age ≥50 years (PR = 3.4; 95% CI: 1.7–6.8), diabetes (PR = 2.0; 95% CI: 1.2–3.4), hypertension (PR = 2.0; 95% CI: 1.3–3.2), current CD4+ cell count <350 cells/mm3 (PR = 2.1; 95% CI: 1.3–3.3), past exposure to tenofovir (PR = 4.7; 95% CI: 2.3–9.4) and past exposure to indinavir (PR = 1.7; 95% CI: 1.0–2.8). As in high-income countries, CKD was the predominant form of kidney involvement among HIV-infected individuals in our setting. The risk factors associated with decreased glomerular filtration were broad and included virus-related factors as well as degenerative and nephrotoxic factors. Despite the potential for nephrotoxicity associated with some antiretroviral drugs, in the short-term, advanced chronic renal disease remains very rare.

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.

Adherence to antiretroviral therapy for HIV/AIDS in Latin America and the Caribbean: Systematic review and meta-analysis

Optimal adherence to antiretroviral therapy is closely related with suppression of the HIV viral load in plasma, slowing disease progression and decreasing HIV transmission rates. Despite its importance, the estimated proportion of people living with HIV in Latin America and the Caribbean with optimal adherence has not yet been reported in a meta‐analysis. Moreover, little is known of the factors leading to poor adherence which may be setting‐specific. We present a pooled estimate of adherence to antiretroviral therapy (ART) of people living with HIV in Latin America and Caribbean, report the methods used to measure adherence and describe the factors associated with poor adherence among the selected studies.

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.

Transmitted drug resistance in patients with acute/recent HIV infection in Brazil

INTRODUCTION The widespread use of antiretroviral therapy increased the transmission of antiretroviral resistant HIV strains. Antiretroviral therapy initiation during acute/recent HIV infection limits HIV reservoirs and improves immune response in HIV infected individuals. Transmitted drug resistance may jeopardize the early goals of early antiretroviral treatment among acute/recent HIV infected patients. METHODS Patients with acute/recent HIV infection who underwent resistance test before antiretroviral treatment initiation were included in this analysis. HIV-1 sequences were obtained using an in house protease/reverse transcriptase genotyping assay. Transmitted drug resistance was identified according to the Stanford HIV Database for Transmitted Drug Resistance Mutations, based on WHO 2009 surveillance list, and HIV-1 subtyping according to Rega HIV-1 subtyping tool. Comparison between patients with and without transmitted drug resistance was made using Kruskal-Wallis and Chi-square tests. RESULTS Forty-three patients were included, 13 with acute HIV infection and 30 with recent HIV infection. The overall transmitted drug resistance prevalence was 16.3% (95% confidence interval [CI]: 8.1-30.0%). The highest prevalence of resistance (11.6%, 95% CI: 8.1-24.5) was against non-nucleoside reverse transcriptase inhibitors, and K103N was the most frequently identified mutation. CONCLUSIONS The high prevalence of nonnucleoside reverse transcriptase inhibitors resistance indicates that efavirenz-based regimen without prior resistance testing is not ideal for acutely/recently HIV-infected individuals in our setting. In this context, the recent proposal of including integrase inhibitors as a first line regimen in Brazil could be an advantage for the treatment of newly HIV infected individuals. However, it also poses a new challenge, since integrase resistance test is not routinely performed for antiretroviral naive individuals. Further studies on transmitted drug resistance among acutely/recently HIV-infected are needed to inform the predictors of transmitted resistance and the antiretroviral therapy outcomes among these population.

Persistent platelet activation and apoptosis in virologically suppressed HIV-infected individuals

Cardiovascular diseases and thrombotic events became major clinical problems in the combined antiretroviral therapy (cART) era. Although the precise mechanisms behind these clinical problems have not been fully elucidated, a persistent pro-inflammatory state plays a central role. As platelets play important roles on both, thrombus formation and inflammatory/immune response, we aimed at investigating platelet function in HIV-infected subjects virologically controlled through cART. We evaluate parameters of activation, mitochondrial function and activation of apoptosis pathways in platelets from 30 HIV-infected individuals under stable cART and 36 healthy volunteers. Despite viral control achieved through cART, HIV-infected individuals exhibited increased platelet activation as indicated by P-selectin expression and platelet spreading when adhered on fibrinogen-coated surfaces. Platelets from HIV-infected subjects also exhibited mitochondrial dysfunction and activation of apoptosis pathways. Finally, thrombin stimuli induced lower levels of P-selectin translocation and RANTES secretion, but not TXA2 synthesis, in platelets from HIV-infected individuals compared to control; and labeling of platelet alpha granules showed reduced granule content in platelets from HIV-infected individuals when compared to healthy subjects. In summary, platelets derived from HIV-infected individuals under stable cART exhibit a phenotype of increased activation, activation of the intrinsic pathway of apoptosis and undermined granule secretion in response to thrombin.

Obesity following ART initiation is common and influenced by both traditional and HIV-/ART-specific risk factors

Background Obesity rates are increasing among HIV-infected individuals, but risk factors for obesity development on ART remain unclear. Objectives In a cohort of HIV-infected adults in Rio de Janeiro, Brazil, we aimed to determine obesity rates before and after ART initiation and to analyse risk factors for obesity on ART. Methods We retrospectively analysed data from individuals initiating ART between 2000 and 2015. BMI was calculated at baseline (time of ART initiation). Participants who were non-obese at baseline and had ≥90 days of ART exposure were followed until the development of obesity or the end of follow-up. Obesity incidence rates were estimated using Poisson regression models and risk factors were assessed using Cox regression models. Results Of participants analysed at baseline (n = 1794), 61.3% were male, 48.3% were white and 7.9% were obese. Among participants followed longitudinally (n = 1567), 66.2% primarily used an NNRTI, 32.9% a PI and 0.9% an integrase strand transfer inhibitor (INSTI); 18.3% developed obesity and obesity incidence was 37.4 per 1000 person-years. In multivariable analysis, the greatest risk factor for developing obesity was the use of an INSTI as the primary ART core drug (adjusted HR 7.12, P < 0.0001); other risk factors included younger age, female sex, higher baseline BMI, lower baseline CD4+ T lymphocyte count, higher baseline HIV-1 RNA, hypertension and diabetes mellitus. Conclusions Obesity following ART initiation is frequent among HIV-infected adults. Key risk factors include female sex, HIV disease severity and INSTI use. Further research regarding the association between INSTIs and the development of obesity is needed.

Early Retention in Care Neither Mediates Nor Modifies the Effect of Sex and Sexual Mode of HIV Acquisition on HIV Survival in the Americas

Abstract Early retention in care, sex, and sexual mode of HIV acquisition has been associated with mortality risk among persons living with HIV (PLWH). We assessed whether early retention in care mediates or modifies the association between mortality and sex and sexual mode of HIV acquisition among PLWH on antiretroviral therapy (ART) in the Americas. ART‐naïve, adult PLWH (≥18 years) enrolling at Caribbean, Central and South America network for HIV epidemiology (CCASAnet) and Vanderbilt Comprehensive Care Clinic sites 2000‐2015, starting ART, and with ≥1 visit after ART‐start were included. Early retention in care was defined as ≥2 HIV care visits/labs ≥90 days apart in the first year of ART. Cox models assessed the association between early retention in care, sex, and sexual mode of HIV acquisition [i.e., women, heterosexual men and men who have sex with men (MSM)], and mortality. Associations were estimated separately by site and pooled. Among 11,721 included PLWH (median follow‐up, 4.3 years; interquartile range, 2.0‐7.6), 647 died (rate = 10.9/1000 personyears) and 1985 were lost to follow‐up (rate = 33.6/1000 person‐years). After adjustment for confounders, early retention in care was associated with lower mortality during subsequent years (pooled hazard ratio = 0.47; 95% confidence interval = 0.39‐0.57). MSM had lower and heterosexual men had comparable mortality risk to women; risks were similar when adjusting for early retention in care. Additionally, no evidence of an interaction between early retention in care and sex and sexual mode of HIV acquisition on mortality was observed (p > 0.05). Early retention in care substantially reduced mortality but does not mediate or modify the association between sex and sexual mode of HIV acquisition and mortality in our population.