1. Oral Abstract WEAB0101
Trends and predictors of non-communicable disease multi-morbidity among HIV-infected adults initiating ART in Brazil,
JL Castilho, MM Escuder, VG Veloso, J Oliveira Gomes, K Jayathilake, S Ribeiro, R Alencar Souza, ML Rodrigues Ikeda, PR de Alencastro,
U Tupinanbas, C Brites, CM McGowan, A Grangeiro, and B Grinsztejn
On behalf of my co-authors, I would like to thank the conference organizers for the opportunity to share the results of our study on the trends and predictors of non-communicable disease multimorbidity among HIV-infected adults initiating ART in Brazil
Vanderbilt University Medical Center
Division of Infectious Diseases
Nashville, TN USA

2. Conflict of Interest
None to declare
I have no conflicts to declare

3. Background
Multi-morbidity from non-communicable diseases is common among aging HIV+ adults on ART
Associated with functional decline, loss of quality of life, and mortality
Coorte Brasil: multi-site observational cohort to examine clinical outcomes of HIV+ adults on ART in Brazil
In high resource settings, it is increasingly recognized that older adults on ART bear heavy burden of multi-morbidity from non-communicable diseases.
Multi-morbidity has been associated with functional decline, loss of quality of life and early mortality in HIV-positive adults.
However, less is known of burden of multi-morbidity in low and middle income countries.
Through support from the Brazilian National Ministry of Health, Coorte Brasil began as a multi-site observational cohort to examine the virologic and clinical outcomes of HIV+ patients starting ART. Over time, it collected data on patients across the country on ART from

4. Methodology
With CCASAnet, non-communicable disease (NCD) outcomes collected and validated from medical records ( )
Outcome: incident multi-morbidity (2 or more cumulative NCDs) after ART initiation
Statistical Approach:
Poisson regression
Cox proportional hazard models
Brazil
Salvador
Belo Horizonte
Rio Preto
In partnership with the Caribbean, Central and South American network for HIV epidemiology (or CCASAnet), NCD diagnoses were collected and validated at 7 clinical sites from 6 cities within the Coorte cohort
For this study, we focused incident multi-morbidity which we defined as the accumulation of 2 or more NCDs following ART initiation. For our analyses, we used poisson regression to examine incidence of NCDs and multimorbidity over time and and cox proportional hazard models to study patient characteristics associated with the development of multi-morbidity
São Paulo
(2 clinics)
Rio de Janeiro
Porto Alegre

5. Cohort N=5,503 (20,976 person-years) 1,796 women (33%)
Incident NCD events N
High-grade hyperlipidemia
437
Diabetes
197
Osteoporosis
107
Coronary artery disease 49
Non-AIDS cancers
Venous thromboembolism 40
Chronic kidney disease 36
Cirrhosis 33
Cerebrovascular disease 28
Osteonecrosis 9
N=5,503 (20,976 person-years)
1,796 women (33%)
Baseline age: 36.6 years
Baseline CD4: 226 cells/mm3
ART regimen: 69% NNRTI
270 (5%) had 1 non-communicable disease (NCD) at baseline
Median follow-up: 3.9 yrs
10% died
In total, we included more than 5,000 adults starting ART whom contributed more than 20K person-years of follow-up
The cohort was 33% female and had a median age of 36 years at ART initiation.
The median CD4 count was 226 cells and nearly 70% of patients started a regimen continaing a non-nucleosidee reverse transcriptase inhibitor
270 patients, or 5%, had one prevalent NCD at the time of ART initaition
The median follow-up time after ART start was close to 4 years and 10% of all patients included died.
Among all participants included, there were 989 incident NCD diagnoses,
The most common NCD was high grade lipid disorders (defined as total cholesterol >300 or LDL >190 or triglycerides greater than 750 mg/dL). The second most frequent NCD was diabetes, followed by osteoporosis or osteopenia. The other NCDs occurred at lower frequencies.

6. NCD Incidence Trends
We first examined the incidence trends of the individual NCDs.
While most NCD diagnoses remained relatively stable during the follow-up period, we observed:
- a trend of decreasing rates of high-grade hyperlipidemia
Increasing rates of diabetes
And rising rates of osteoporosis and osteopenia
In the latter years of observation

7. Multi-morbidity Incidence
While rates of individual NCDs were stable in many cases, the rates of incident multi-morbidity with 2 or more (as seen in the orange line) or 3 or more NCDs (in the green line) significantly increased during the study period.

8. Multi-morbidity Incidence
This rise in the incidence of multi-morbidity paralleled the increasing proportion of person-time in the cohort that was comprised of adults ages 50 years or greater. By 2014, more than 20% of the cohort was over the age of 50 years.

9. Female Sex 1.36 1.05-1.77 0.020 aHR* 95% CI p value
We next examine the demographic and clinical characteristics associated with incident multi-morbidity following ART initiation. We found that females had an increased cumulative incidence of multi-morbidity compared to males. In multivariable Cox models that adjusted also included site, age, race, education, CD4 nadir, hepatitis C infection, calendar year, and prevalent NCD at baseline, the statistically significant increased risk associated with female sex remained.
* Adjusting for site, race, sex, age, education, CD4 nadir, hepatitis C, year, & prevalent NCD

10. aHR* 95% CI p value Baseline Age < 30 years 30-39 years 40-49 years
Ref
1.41
2.97
6.16
0.229
<0.001
In addition to sex, older age at ART initiation was also associated with increased risk of multi-morbidity. In adjusted analyses, patients over the age of 50 at ART initiation had a 6-fold increased risk of multi-morbidity compared to those under 30.
* Adjusting for site, race, sex, age, education, CD4 nadir, hepatitis C, year, & prevalent NCD

11. CD4 cell count nadir > 200 cells/mm3 100-199 < 100 Ref 1.64 1.76
aHR*
95% CI
p value
CD4 cell count nadir
> 200 cells/mm3
< 100
Ref
1.64
1.76
0.002
<0.001
Finally, we also found history of low CD4 nadir was associated with increased risk of multi-morbidity. This association persisted in multivariable analyses controlling for other confounders.
* Adjusting for site, race, sex, age, education, CD4 nadir, hepatitis C, year, & prevalent NCD

12. NCD diagnoses of multi-morbidity patients
Males (n=167, 380 diagnoses)
Females (n=121, 280 diagnoses) 6%
15%
35%
40%
26%
To explore the role of sex further, we examined the NCD diagnoses among those patients with incident multi-morbidity by sex. Of the 288 patients with incident multi-morbidity, 167 were males and 121 were females. The males who developed multi-morbidity had a total of 380 incident NCD diagnosis and the females had a total of 280 NCDs. For both men and women, hyperlipidemia was the most common diagnosis observed, accounting for 40% of the diagnoses in males and 35% of the diagnoses in females. After hyperlipidemia, diabetes was the most frequent, accounting for approximately a quarter of diagnoses in males and females. However, osteoporosis or osteopenia was the third most frequent NCD in females, accounting for 15% of all diagnoses, while only contributed 6% of diagnoses in males with multi-morbidity.
24%

13. Limitations
No uniform definition of multi-morbidity or non-communicable diseases in HIV literature
May be missing other important co-morbidities
Lack of important behavioral (including tobacco and alcohol use) and body mass index data
Observational data and variation of clinical practices and documentation across sites
Our study has some important limitations to consider.
First, there is no uniformly accepted list of NCDs in the literature from which to build a definition of multimorbidity and we elected to focus on outcomes of end-organ disease or those which could be reliably collected and validated from laboratory data. We did not have validated diagnoses of hypertension, pulmonary disease, or psychiatric diseases which may be important contributors to multi-morbidity in aging HIV-positive adults.
Additionally, we did not have data from all sites on important behavioral factors such as tobacco and alcohol use. Nor were data regarding height and weight available to construct BMI. It is possible that these factors contributed to confounding that was not accounted for in our models.
Finally, while we statistically sought to account for differences, this study was observational and limited to what was available in medical records and subject to variability across sites.

14. Strengths ART widely available in Brazil since 1996
National systems for ART tracking and laboratory monitoring
Multi-site cohort with geographic and clinical diversity
Validated non-communicable disease outcomes
With those limitations recognized, this study also presents important strengths as a multi-site cohort study of NCDs and multi-morbidity in a middle-income country.
Brazil is a unique and important setting to study NCDs and aging outcomes in HIV given it’s wide availability of ART since 1996.
Observational research in Brazil is strengthened by its national databases on ART and laboratory monitoring
This multi-site study is built upon a country with rich geographic and clinical diversity
And lastly, this study is strengthened by the additional processes of rigorous validation of NCD outcomes included.

15. Conclusions
Multi-morbidity from non-communicable diseases is increasing among aging adults on ART in Brazil
After adjusting for CD4 and age, female sex was independently associated with increased risk
Hyperlipidemia and diabetes account for majority of non-communicable disease co-morbidities
Osteoporosis increasingly contributes to multi-morbidity, particularly in females
In conclusion, we found that

16. Acknowledgements
Vanderbilt University (Nashville, USA) Stephany Duda Bryan Shepherd São Paulo State Department of Health, (São Paulo, Brazil) Guilherme Berto Calvinho Angelica Marta Lopes Claudia di Maria Medori Mafredo Care and Treatment Clinic of the Partenon Sanatorium (Porto Alegre, Brazil) Sonia Maria de Alencastro Coracini Claudia Penalvo Gabriela Almeida Edgar Santos University Hospital Complex (Salvador, Brazil) Estrela Luz
AIDS Reference and Training Center (São Paulo, Brazil)
Anita Sevzatian Terzian
Gabriela R. Waghabi
Rejane Alves Fraissat
Funding Sources:
Brazilian National Council for Scientific & Technological Development
Brazilian National Ministry of Health
- Pan American Health Organization
- NIH K23AI
- NIH u01AI69923
Lastly, I would like to acknowledge the many individuals who contributed to this work and our funders. With that I will take any questions.